Prenatal Exposure To Air Pollution And Pre-Labor Rupture Of Membranes In A Prospective Cohort Study: The Role Of Maternal Hemoglobin And Iron Supplementation

ObjectiveWe aimed to identify the sensitive time-windows of exposure to air pollution for PROM risk.Further,we examined whether maternal hemoglobin levels mediate the association between exposure to air pollution and PROM,as well as investigated the potential effect of iron supplementation on this association.MethodsFrom 2015 to 2021,6824 mother-newborn pairs were enrolled in the study from three hospitals in Hefei,China.We obtained air pollutant data(PM_2.5,PM₁₀,SO₂,and CO)from the Hefei City Ecology and Environment Bureau.Information on maternal hemoglobin levels,gestational anemia,iron supplementation,and PROM was obtained from medical records.Logistic regression models with distributed lags were used to identify the sensitive time-window for the effect of prenatal exposure to air pollutant on PROM.Mediation analysis estimated the mediated effect of maternal hemoglobin in the third trimester,linking prenatal air pollution with PROM.Stratified analysis was used to investigate the potential effect of iron supplementation on PROM risk.ResultsOf the 6,824 women who agreed to participate in the study,1,439（21.1%）had PROM.Women with PROM were more likely to be younger and to have a lower frequency of folic acid supplementation during pregnancy than those without PROM Compared with women without PROM,higher proportions of primipara,GDM,gestational anemia,and delivery in winter and spring were observed in women with PROM The excluded women had incomplete covariates on birth outcomes,higher proportion of giving birth in winter and spring.Strong correlation between 4 air pollutants in three trimesters was observed（Spearman correlation ranged from 0.01 to 0.94）（Supplementary Table 2）.The mean（SD）gestational exposure to PM_2.5,PM₁₀,SO₂,and CO in the second and third trimester was 54.2 μg/m³（15.1）,83.2 μg/m³（13.5）,11.8 μg/m³（4.0）,and 0.9 mg/m³（0.2）.The weekly air pollutant exposures were significantly associated with increased PROM risk: the windows of susceptibility for PM_2.5（per 10 μg/m³ increase）was between gestation weeks（GW）15 and 37,the maximum effect was in 21th-23 th GW for PM₁₀（per 10 μg/m³ increase）was between GW 18 and 32,the maximum effect was in 24 th GW;for SO₂（per 5 μg/m³）between GW 10 and 37,the maximum effect was in 21 th GW;and for CO（per 0.1 mg/m³）was between GW 13 and 31,the maximum effect was in 21th-24 th GW.The estimated cumulative risk of PROM was significantly associated with prenatal exposure to air pollutants throughout the second and third trimesters（Table 2）.For example,the cumulative OR for the second and third trimester was 1.13 per 10 μg/m³ increase in PM_2.5（95% CI:1.06,1.22）.Similarly,significant associations were observed with per 10 μg/m³ increase in PM₁₀ [OR = 1.18（95% CI:1.10,1.27）],per 5 μg/m³ increase in SO₂ [OR = 1.16（95% CI: 1.06,1.28）],and per 0.1 mg/m³ increase in CO [OR = 1.10（95% CI:1.04,1.15）].Effect of each air pollutant(per 10 μg/m³ in PM_2.5 and PM₁₀,per 5 μg/m³ in SO₂,and per 0.1 mg/m³ in CO)throughout the second trimester and third trimester,was negatively associated with low maternal hemoglobin levels in third trimester [β with 95% CI for PM_2.5:-0.94 g/L（-1.15,-0.73）;β with 95% CI for PM₁₀:-1.31 g/L（-1.55,-1.07）;β with 95% CI for SO₂:-2.96 g/L（-3.32,-2.61）;and β with 95% CI for CO:-1.11 g/L（-1.31,-0.92）] upon adjusting for age,education,income,activity,passive smoking,iron supplementation,pre-pregnancy BMI,hypertension during pregnancy,gestational diabetes mellitus,and temperature.After adjusting for age,education,income,parity,activity,passive smoking folic acid supplementation,iron supplementation,pre-pregnancy BMI,hypertension during pregnancy,gestational diabetes mellitus,vaginitis,and temperature,higher risk of PROM was observed in women with hemoglobin below 100 g/L（OR,2.44;95% CI:1.73,3.46）,women with a hemoglobin range of 100-104 g/L（OR,2.42;95% CI:1.72,3.41）,women with a hemoglobin range of 105-109 g/L（OR,2.40;95% CI:1.73,3.34）,women with a hemoglobin range of 110-114 g/L（OR,1.97;95% CI:1.42,2.73）,women with a hemoglobin range of 115-119 g/L（OR,1.77;95% CI:1.27,2.45）,women with a hemoglobin range of 120-124 g/L（OR,1.72;95% CI:1.23,2.42）,and women with a hemoglobin range of 125-129 g/L（OR,1.52;95% CI:1.05,2.21）when compared with that in women in the conference group（hemoglobin higher than 130 g/L）.Maternal hemoglobin levels in the third trimester mediated20.61%（AME = 0.02,95% CI: 0.01,0.05）of the contribution to the association of principal component of exposure to air pollutants throughout the second and third trimesters with PROM after adjusting for age,education,income,parity,activity,passive smoking,folic acid supplementation,iron supplementation,pre-pregnancy BMI,hypertension during pregnancy,gestational diabetes mellitus,vaginitis,and temperatureData presented in our study show that the risk of PROM was significantly attenuated by iron supplementation during pregnancy in women with gestational anemia under low-medium exposure to air pollution in adjusted and unadjusted model.Iron supplementation in women with low-medium exposure to air pollution resulted in a significantly lower incidence of PROM than that seen in women without iron supplementation.For PM_2.5,our analysis indicated a pattern toward lower incidence of PROM in women who were taking iron supplements compared to that in women not taking iron supplements under low medium air pollution（16.0% vs.18.5%）and high air pollution（21.4% vs.23.4%）.Conclusion:Prenatal exposure to ambient air pollution(PM_2.5,PM₁₀,SO₂,and CO),especially in 21 th to 24 th week of pregnancy,is positively associated with PROM risk,partly mediated by maternal hemoglobin levels.Iron supplementation in anemia pregnancy potentially has a potential positive association on low-medium air pollution-related PROM.Screening and treatment of gestational anemia could provide novel insights into the prevention of low-medium air pollution-related PROM.