Association Of Ambient Air Pollution Exposure With Fertility Potential Among Childbearing Aged Women In Shanxi Province

In recent years,women infertility has been increasing year by year around the world,leading to sharply declined birth rate.Up to now,the proportion of infertile population in China has dramatically risen.Therefore,the decline in women fertility poses serious challenge to population development.Substantially,the births number in China dropped from more than 17 million in 2016 to 9.56 million in 2022.Reduced fertility of reproductive aged women poses threat to population stabilization and sustainable development of economy.Rapid urbanization development brought severe air pollution,which has adverse effect on women reproductive health in modern society.Existing epidemiological studies have reported that maternal exposure to ambient air pollution has adverse effect on maternal and fetal health.However,the association of exposure to ambient air pollution outside the prenatal period with female fertility potential is scarce.In this study,Shanxi province was regarded as the study area,and the reproductive aged women residing in eleven prefectural level cities of Shanxi were regarded as the subjects.Based on physiological characteristics of the whole reproductive life cycle,antral follicule count,reproductive hormones,menstrual cycle rhythmicity,and ovarian response were selected as fertility potential pridictors,which were the target outcomes exposed to ambient air pollution.The association of exposure to ambient air pollution and women fertility potential was conducted.This study has important public health significance and guiding value for promoting regional air pollution governance and effectively protecting fertility potential of fertile women.The detailed research contents were shown as follows.1.In this chapter,atmospheric pollution during the period from 2013 to 2020 in Shanxi province was evaluated,and the retrospective study population of childbearing aged women in Shanxi was established.Atmospheric pollutants concentration data between January 2013 and December 2020 from eleven prefecture-level cities including Datong,Yangquan,Lvliang,Xinzhou,Jinzhong,Shuozhou,Jincheng,Yuncheng,Linfen,Taiyuan,Changzhi in Shanxi was collected from local air quality monitoring sites.The results showed that air pollution in Shanxi was severe before 2018 and has a characteristic of soot air pollution and seasonal alternation.The concentrations of particulates,SO₂,NO₂in autumn and winter were higher,while lower in summer.However,O₃ concentration in summer was higher,and lower in winter and autumn.Since 2018,the concentrations of PM₁₀,PM_2.5 and SO₂ decline annually.Until 2019,air quality in Shanxi has improved significantly.However,atomospheric NO₂concentration is increasing year by year,and ozone concentration also increase annually.The regions of higher concentration of NO₂,PM₁₀,PM_2.5 and SO₂were Taiyuan Basin,Xinding Basin,Linfen Basin,Yuncheng Basin and Lvliang region.Although concentrations of particulates were decreasing,the levels were not stable.At the same time,higher concentration level of ozone in summer gradually become severe,especially severe in southeast area such as Linfen and Jincheng in Shanxi.726 women of reproductive age who were permanent residents in Shanxi were recruited as the study subjects to participate in this study.2.In this chapter,the association of ambient air pollution exposure with antral follicule development was analysed.Antral follicles count（AFC）was regarded as the outcome of ambient air pollution to predict women reproductive potential.Based on follicle physiological development characteristics,exposure timeline window of air pollution was designed for AFC.Three distinct stages corresponding to the development process of antral follicle were separately regareded as the three exposure windows,including six months as period 1 starting from primary small follicle to antral follicle,four months as period 2 starting from primary small follicle to preantral follicle and two months as period 3 starting from preantral follicle to antral follicle.Based on the relatively long timeline of follicule development process,monthly concentrations of air pollutants were calculated as the exposure levels.Generalized linear model（GLM）was employed to retrospectively analyze the association between air pollution exposure and AFC of these women.The results suggested that increased exposure levels of atmospheric SO₂ was associated with decreased AFC（-0.01;95CI:-0.016,-0.002）after adjusting for the confounders.Compared to Q1 group,SO₂ level of Q4 group was negatively significantly with AFC（-0.066;95%CI:-0.125,-0.007）.During period 2,increased level of SO₂ was associated with decreased AFC（0.01;95%CI:-0.015,-0.002）,indicating that the early transition stage from primary to preantral follicle may be the sensitive stage of air pollution exposure.Moreover,the negative association of SO₂ exposure with AFC among the women of 30 years old was especially pronounced（Period1:-0.011,95CI:-0.021,-0.002;Period2:-0.01,95CI:-0.02,-0.002）.The association was still significant in sensitivity analyses.This finding revealed that long-term exposure to atmospheric SO₂was associated with lower AFC,raising our concern that soot air pollution exposure has adverse impact on women ovarian reserve.No significant associations of NO₂,PM₁₀,PM_2.5,CO and O₃exposure with AFC were observed in this study.3.In this chapter,the associations of ambient air pollution exposure with women reproductive hormones were analysed.Women reproductive hormones including Anti-mullerian hormone（AMH）,basal follicule stimulating hormone（FSH）and basal estradiol（E₂）were regarded as outcome indicators in this section,and cross-sectional cohort study was conducted.The information of AMH,basal FSH and basal E₂ in peripheral blood serum of subjects on the menstrual bleeding days from the second day to the forth day was collected.Air pollution exposure windows for AMH,FSH and E₂ levels were designed based on physiological regulation of female hypothalamic-pituitary-ovarian axis and the charicteristics of granulosa cells secreting AMH.GLM was used to evaluate the associations of air pollution exposure on reproductive hormones among women of childbearing age.The results suggested that exposure to high concentrations of atmospheric NO₂ were significantly associated with lower AMH levels among these women during five distinct periods of follicular development（Period 1:-0.217,95%CI:-0.375,-0.062;Period2:-0.310,95%CI:-0.468,-0.152;Period3:-0.269,95%CI:-0.432,-0.107;Period4:-0.277,95%CI:-0.440,-0.104;Period5:-0.192,95%CI:-0.361,-0.023）.The results of NO₂ exposed association with AMH were relatively robust in sensitivity analyses,indicating that atmospheric NO₂ may have independent association with female reproductive hormones.In addition,negative association of air pollution exposure with AMH was particularly significant among women younger than 35 years old compared to the younger women(P_-trend=0.001).Although higher level of SO₂ was significantly associated with lower AMH,the result was not as robust as that of NO₂.No significant association of PM₁₀,PM_2.5,CO,O₃ with AMH,as well as with basal FSH and E₂was observed.The result revealed that atmospheric NO₂ exposure have independent association with female AMH hormone,which may accelerate female reproductive aging.4.In this chapter,the associations of ambient air pollution exposure with menstrual cycle lengths were analysed.Menstrual cycle diaries and ovulation test strips were sent to the study women and asked them to record daily menstrual cycle characteristics including total length of menstrual cycle,follicular phase length,luteal phase length,and the risk of dysmenorrhea.Exposure windows for menstrual cycle lengths and dysmenorrhea were separately designed based on physiological characteristics of menstrual cycle,including the follicular phase of last menstrual cycle as period 1,the luteal phase of last menstrual cycle as period 2,and the entire phase of last menstrual cycle as period 3.GLM was used to evaluate the associations of air pollution exposure on these menstrual cycle lengths and the risk of dysmenorrhea.The results showed that high concentrations of atmospheric SO₂（Period1:0.053,95CI:0.022,0.083;Period2:0.049,95CI:0.02,0.078;Period3:0.045,95CI:0.017,0.073）and NO₂（Period1:0.039,95CI:0.011,0.068;Period2:0.029,95CI:0.01,0.057;Period3:0.035,95CI:0.006,0.065）were significantly positively associated with total menstrual cycle length.Moreover,the positive association of ambient SO₂exposure with total length of menstrual cycle present significantly linear prend(P_-trend=0.001).Furthermore,the positive association of high concentrations of atmospheric SO₂（0.038;95CI:0.015,0.061）and NO₂（0.060;95CI:0.035,0.085）exposure with total menstrual cycle length mainly present the prolongation of follicular phase length.O₃ exposure level in Q4 group were significantly associated with shortened follicular phase during period 1（-0.043;95%CI:-0.079,-0.003）,period 2（-0.047;95%CI:-0.072,-0.022）,and period 3（-0.046;95CI:-0.081,-0.011）.Additionlly,employment and educational level modified the association of SO₂ with total menstrual cycle length,this association was particularly stronger among women who were not employed（0.024;95CI:0.008,0.040）or with low educational level（0.019;95CI:0.009,0.030）.However,employment and educational level have no significant modification on the assocaition of NO₂ exposure with total menstrual cycle length and follicular length.This result indicated that follicule phrase of menstrual cycle was the sensitive period and atmospheric air pollution has influence on menstrual cycle regularity.5.In this chapter,the associations of ambient air pollution exposure with ovarian response were analysed.For the women who underwent controlled ovarian stimulation（COS）treatment,timely follicular monitoring and follow-up were orderly conducted.Ovarian response follicle output rate（FORT）was selected as the evaluated reproductive predictors.Exposure windows for FORT were designed from the day of COS starting to the day of oocyte retrival.Generalized estimation equation（GEE）was used to evaluate the association of air pollution exposure on FORT.The results showed that higher concentration levels of atmospheric SO₂（-0.057;95CI:-0.097,-0.017）were significantly associated with lower FORT.Compared to Q1 group,SO₂exposure level in Q4 group was negeatively significantly associated with FORT（-0.097;95%CI:-0.172,-0.022）.women age did not affect the negative association of SO₂ exposure with FORT in stratification analyses（<35 years:-0.054,95CI:-0.097,-0.011;≥35 years:-0.128,95CI:-0.200,-0.057）.The association of SO₂ exposure with FORT was still significant among the women undergoing the first COS（-0.107;95CI:-0.183,-0.031）,as well as significant when further adjusting estrogenon trigger day（-0.102;95CI:-0.175,-0.030）.the association of SO₂ exposure with FORT was still robust in two pollution model.The finding suggested that atmospheric SO₂ exposure may have independently association on ovarian response among COS women.There were no significant associations of NO₂,PM₁₀,PM_2.5,CO and O₃exposure with FORT.Combined the regional situation of ambient air pollution in our country,this study comprehensively evaluated the association of ambient air pollution exposure with fertility potential of childbearing aged women by assessing distinct fertility indicators,including antral follicle development,reproductive hormones,menstrual cycle lengths,ovarian response.The achieved results suggested that higher exposure levels of atmospheric pollution have potential association with follicular development,ovarian reserve,menstrual cycle regularty and ovarian response.This result revealed that regional ambient air pollution has potential association with female fertility.The finding provides imperative epidemiological evidences of the issue of regional air quality protection policy,scientific formulation of prevention strategies for women fertility potential.The achieved results in this study have of great public health significance.