不同暴露窗口空气污染对体外受精妊娠结局的影响

Association between ambient air pollution and pregnancy outcomes in women undergoing in vitro fertilization

目的探讨不同窗口期空气污染物暴露水平与体外受精(in vitro fertilization,IVF)/卵胞质内单精子注射(intracytoplasmic sperm injection,ICSI)患者妊娠结局之间的关系,并探索对空气污染物暴露敏感的时间窗。方法对2014年1月至2021年12月期间在哈尔滨医科大学附属第一医院生殖医学科接受首次新鲜卵裂期胚胎移植的2071例40岁以下不孕症患者的资料进行回顾性队列研究。按促性腺激素(gonadotropin,Gn)启动日是否供暖将患者分为供暖季组和非供暖季组,比较两组的基线资料和妊娠结局。按IVF/ICSI治疗时间线划分为4个离散的暴露时间窗:暴露窗1,即Gn启动前75 d到Gn启动日;暴露窗2,即Gn启动日到取卵前一天;暴露窗3,即取卵日到第3天胚胎移植日;暴露窗4,即胚胎移植日到血清人绒毛膜促性腺激素检测日。分别计算每个患者在各个暴露窗口期6种空气污染物[细颗粒物(fine particulate matter,PM_(2.5))、可吸入颗粒物(inhalable particulate matter,PM_(10))、二氧化氮(nitrogen dioxide,NO_(2))、二氧化硫(sulfur dioxide,SO_(2))、一氧化碳(carbon monoxide,CO)和臭氧(ozone,O_(3))]的日平均水平。主要结局指标是持续妊娠率。采用多因素逻辑回归模型研究不同暴露窗口期的空气污染物暴露水平与妊娠结局之间的关联,并针对重要的混杂因素进行调整。结果供暖季组的生化妊娠率[51.7%(465/900)]、临床妊娠率[45.2%(407/900)]、持续妊娠率[38.2%(344/900)]和活产率[36.1%(325/900)]均显著低于非供暖季组[56.3%(659/1171),P=0.037;51.2%(599/1171),P=0.007;44.3%(519/1171),P=0.005;41.3%(484/1171),P=0.016]。在4个时间窗都可以观察到SO_(2)和NO_(2)暴露与持续妊娠呈显著负相关,SO_(2)每增加一个四分位间距(interquartile range,IQR),对应aOR和95%CI分别为0.92(0.85~0.99)、0.92(0.87~0.99)、0.93(0.87~0.99)和0.93(0.87~0.99)。对于NO_(2),每个IQR增量的aOR和95%CI分别为0.83(0.72~0.95)、0.87(0.77~0.97)、0.90(0.81~1.00)和0.85(0.77~0.95)。在暴露窗1和4,PM10暴露与持续妊娠可能性降低显著相关(aOR=0.86,95%CI:0.75~0.98;aOR=0.89,95%CI:0.80~1.00)。在暴露窗1,PM2.5暴露与持续妊娠呈显著负关联(aOR=0.86,95%CI:0.75~0.99)。此外,在除暴露窗3之外的所有暴露窗口中都观察到NO_(2)暴露与临床妊娠失败显著相关(暴露窗1:aOR=0.85,95%CI:0.74~0.97;暴露窗2:aOR=0.88,95%CI:0.79~0.99;暴露窗4:aOR=0.89,95%CI:0.81~0.99)。没有显示CO和O_(3)对妊娠结局的影响。结论空气污染物暴露会降低IVF/ICSI鲜胚移植周期持续妊娠的可能性,并且在IVF助孕之前的窦前卵泡到窦卵泡阶段,这种影响同样存在。在几乎所有暴露窗口中都观察到,NO_(2)暴露与临床妊娠和持续妊娠失败显著相关,提示NO_(2)可能是与IVF妊娠结局相关的主要空气污染物。

Objective To investigate the association between exposure to ambient air pollutants and pregnancy outcomes in patients undergoing in vitro fertilization(IVF)/intracytoplasmic sperm injection(ICSI),and to clarify the susceptible windows of exposure.Methods A retrospective cohort study was conducted on 2071 infertile women aged≤40 years who underwent the first fresh cleavage stage embryo transfer in the Department of Reproductive Medicine of the First Affiliated Hospital of Harbin Medical University from January 2014 to December 2021.Patients were divided into heating season group and non-heating season group based on whether the start date of gonadotropin(Gn)was during the heating season or not,and baseline data and pregnancy outcomes were compared between the two groups.Daily average levels of six criteria air pollutants[fine particulate matter(PM_(2.5)),inhalable particulate matter(PM_(10)),nitrogen dioxide(NO_(2)),sulfur dioxide(SO_(2)),carbon monoxide(CO),ozone(O_(3))max-8 h]in four discrete periods were obtained.The four discrete periods included period 1,75 d prior to Gn start to Gn start;period 2,Gn start to oocyte retrieval;period 3,oocyte retrieval to day 3 embryo transfer;period 4,embryo transfer to serum human chorionic gonadotropin test.The primary outcome was ongoing pregnancy.A multiple logistic regression model was used to investigate the association between air pollutant exposure and pregnancy outcomes,adjusted for important confounders.Results The biochemical pregnancy rate[51.7%(465/900)],the clinical pregnancy rate[45.2%(407/900)],the ongoing pregnancy rate[38.2%(344/900)],and the live birth rate[36.1%(325/900)]in the heating season group were significantly lower than those in the non-heating season group[56.3%(659/1171),P=0.037;51.2%(599/1171),P=0.007;44.3%(519/1171),P=0.005;41.3%(484/1171),P=0.016].A significant negative correlation was observed between SO_(2) and NO_(2) exposure and ongoing pregnancy in all four time windows.SO_(2) increased by one interquartile range(IQR),corresponding to adjusted OR(aOR)and 95%CI were 0.92(0.85-0.99),0.92(0.87-0.99),0.93(0.87-0.99)and 0.93(0.87-0.99),respectively.An IQR increase in NO_(2) was also significantly associated with decreased odds of ongoing pregnancy(aOR=0.83,95%CI:0.72-0.95;aOR=0.87,95%CI:0.77-0.97;aOR=0.90,95%CI:0.81-1.00;aOR=0.85,95%CI:0.77-0.95,respectively).During period 1 and period 4,we observed adverse effects of PM10 exposure on ongoing pregnancy(aOR=0.86,95%CI:0.75-0.98;aOR=0.89,95%CI:0.80-1.00,respectively).In Period 1,PM2.5 exposure was significantly associated with reduced odds for ongoing pregnancy with aOR=0.86,95%CI:0.75-0.99.In addition,NO_(2) exposure was associated with a decreased likelihood of achieving clinical pregnancy across all exposure windows except for period 3.However,no associations were noted with CO and O_(3).Conclusion Ambient air pollution has detrimental effects on pregnancy outcomes in patients undergoing fresh embryo transfer.Notably,the adverse impacts were also observed during preantral-antral follicle transition stage before IVF/ICSI treatment.A significant negative association between NO_(2) exposure and pregnancy outcomes was observed in almost all exposure windows,indicating that NO_(2) may be the main air pollutant associated with adverse pregnancy outcomes.