| Hypertensive disorders of pregnancy(HDP)are the main factors leading to poor prognosis of pregnant women and newborns,and they are related to increased risk of cardiovascular disease in the later stage of offspring.The changes in blood pressure during pregnancy have different types of trajectories,the blood pressure of pregnant women would show high-stable or fast-increasing and other high-risk trajectories before reaching the HDP diagnostic threshold,and it was difficult to identify HDP in time only by evaluating the blood pressure at a single time point.Therefore,it is of great significance to identify the high-risk blood pressure trajectories related to the risk of HDP for early detection of highrisk groups of HDP.Epidemiological studies have shown that exposure to toxic metals such as cadmium(Cd),lead(Pb),mercury(Hg),and nickel(Ni)were associated with higher levels of blood pressure and increased risk of HDP,but the results are inconsistent and the impacts of metal mixtures have not been well characterized.Most studies only evaluated the correlation between metals and the change in mean blood pressure during pregnancy.It is unclear whether single or combined exposure to metals during pregnancy will increase the occurrence of HDP high-risk blood pressure trajectories.In addition,pregnant women with HDP had pathophysiological changes before 20 weeks of pregnancy.Therefore,it is necessary to identify changeable exposure markers in early pregnancy and explore their relationship with HDP risk and high-risk blood pressure trajectory.Currently,the pathogenesis of HDP is unclear.Studies have shown that pre-pregnancy overweight or obesity may be related to changes in blood pressure during pregnancy and the risk of HDP.Pregnancy body mass index(BMI)was an important indicator to reflect the nutritional status of mothers during early pregnancy.Many studies have found that changes in fatty acid metabolism might be associated with changes of blood pressure leves or increase the risk of hypertension and cardiovascular disease.In addition,exposure to metals such as aluminum(Al),Cd,and Hg may lead to abnormal fatty acid metabolism.At present,it is not clear whether fatty acids play a mediating role in the relationship between exposure to metals during early pregnancy and HDP risk.Considering the available evidence,we conducted this study based on a longitudinal cohort study to identify the high-risk of blood pressure trajectory associated with increased risk of HDP,and further analyze its influencing factors.We measured the concentrations of metals in the plasma sampled in the first trimester to explore the overall effects of exposure to multiple metals during early pregnancy on the high-risk blood pressure trajectory of HDP and the risk of HDP.In addition,we explored the impact of exposure to metals during early pregnancy on the levels of fatty acids,and further explored the role of fatty acids in the association between exposure to metals during early pregnancy and the risk of HDP.Part Ⅰ Predictors of Hypertensive Disorder of Pregnancy Related Blood Pressure TrajectoryObjectives: Based on a prospective cohort study,to identify the trajectory of blood pressure changes during pregnancy,assess the high-risk blood pressure trajectories associated with increased risk of HDP and further investigate its related influencing factors.Methods: Based on the prospective cohort established in Wuhan,7 084 pregnant women recruited from August 2012 to March 2017 were included in the final analysis.The blood pressure follow-up data originated from prenatal examination(< 16 weeks of gestation)was obtained.Blood pressure data recorded at least 3 times during 5 periods of pregnancy were selected.The latent class growth model was used to fit the blood pressure trajectory during pregnancy,to identify the high-risk blood pressure trajectories associated with increased risk of HDP,and to further explore the influencing factors(maternal age and pre-pregnancy BMI)associated with blood pressure trajectory.Results: The incidence of HDP was 5.55%.Five systolic blood pressure(SBP)and diastolic blood pressure(DBP)trajectory groups and four mean arterial pressure(MAP)trajectory groups were identified among the study population.Pregnant women with medium-low-fast increasing and high-increasing trajectory of SBP had significantly higher risk of HDP(OR = 1.51,95%CI: 1.09,2.08;OR = 22.11,95% CI: 17.23,28.37).Pregnant women with medium-fast increasing and high-stable trajectory of DBP had significantly higher risk of HDP(OR = 2.14,95% CI: 1.69,2.71;OR = 9.67,95% CI: 7.76,12.05).Pregnant women with medium-low-fast increasing and high-increasing group trajectory of MAP were significantly higher risk of HDP(OR = 1.50,95% CI: 1.10,2.04;OR = 14.11,95% CI: 11.14,17.87).Pregnant women who were older,had pre-pregnancy BMI < 18.5kg/m2 or ≥ 24.0 kg/m2,excessive weight gain during pregnancy,primiparity,lower annual household income levels(< 100 000 RMB),and reported passive smoking during pregnancy were more likely to have HDP high-increasing blood pressure trajectories(SBP mediumlow-fast increasing and high-increasing trajectory,DBP medium-fast increasing and highstable trajectory,and MAP medium-low-fast increasing and high-stable trajectory).Conclusions: Pregnant women with low-fast increasing and high-increasing trajectories of SBP,DBP,and MAP during pregnancy had a higher risk of HDP.Overall,older maternal age,pre-pregnancy BMI < 18.5 kg/m2 or ≥ 24.0 kg/m2,excessive weight gain during pregnancy,primiparous women,low maternal education,and low annual household income levels were associated with increased risk of HDP-related blood pressure trajectory.Part Ⅱ Association between Plasma Metal Levels of Pregnant Womenand High-Risk Blood Pressure Trajectory during PregnancyObjectives: To investigate the association between single and mixed metals in early pregnancy and high-risk blood pressure trajectories,to identify the metal with the greatest contribution weight in the association.The joint effect between pre-pregnancy BMI or age and metal exposure on the risk of HDP with the associations was further investigated.Methods: The study population originated from Part 1,3 618 pregnant women who provided plasma samples during early pregnancy from October 2013 to June 2015 were included.The concentrations of 11 metals in maternal plasma samples were determined by inductively coupled plasma mass spectrometry.Multinomial logistic regression models were used to assess the associations between plasma concentrations of metals and the highrisk blood pressure trajectories.The weighted quantile sum(WQS)regression model was used to investigate the impacts of mixed metal exposure on high-risk blood pressure trajectories and to identify the metal with the largest contribution weight in the association.The relative excess risk due to interaction(RERI)was calculated to evaluate the additive interaction effects between pre-pregnancy BMI and metal exposure in early pregnancy on HDP risk-related blood pressure trajectory.Results: After adjusting for confounding factors,the results of multiple logistic regression analysis showed that higher plasma copper concentrations were significantly associated with an increased possibility of a low-fast increasing trajectory of SBP,and Hg and Ni were significantly associated with an increased possibility of a high-increasing trajectory of SBP.Cd and Hg were significantly associated with an increased possibility of a high-stable trajectory of DBP.Al,Cd,Hg,and Ni were significantly associated with the increased possibility of a high-increasing trajectory of MAP.In the WQS regression model,the plasma concentration of metals mixture in the first trimester was positively associated with a low-fast rising trajectory of SBP(OR = 1.35,95% CI: 1.20,1.50),among which Hg(35.9%)and Pb(30.5%)accounted for the largest weight.Metal mixture was associated with the possibility of a high-increasing trajectory of SBP during pregnancy increased(OR= 1.80,95% CI: 1.18,2.75),among which Al(32.6%)and Hg(23.8%)accounted for the largest weight.Metal mixture was associated with the possibility of a high-increasing trajectory of DBP during pregnancy increased(OR = 1.46,95% CI: 1.20,1.78),among which Hg(42.6%)and Al(13.8%)accounted for the largest weight.Metal mixture was associated with the possibility of a high-increasing trajectory of MAP during pregnancy increased(OR = 1.58,95% CI: 1.35,1.83),among which Hg(37.9%)and Al(18.9%)accounted for the largest weight.A positive additive interaction effects between higher pregnancy BMI and Hg(RERI: 1.49,95% CI: 0.34,2.63)on the low-fast rising mode of DBP,the high-increasing trajectory of MAP exposed to Hg(RERI:0.80,95% CI: 0.10,1.46)and Ni(RERI: 0.70,95% CI: 0.01,1.37).Conclusion: Mixed metal exposure in early pregnancy was significantly associated with an increased risk of the probability of high-risk blood pressure trajectories.The metals with greater weight include Al,Pb,and Hg.Higher pre-pregnancy BMI and exposure to Al,Hg,and Ni exposure may have a positive additive interaction on high-risk blood pressure trajectories.Part Ⅲ Association of Maternal Plasma Metal Levels with HypertensiveDisorders of PregnancyObjective: To investigate the associations between exposure to single and multiple metals n early pregnancy and the risk of HDP.To explore the mediation role of fatty acids in the associations of metal exposure with the developing HDP.Methods:(1)Like Part 2,126 pregnant women were diagnosed with HDP,and 3 492 pregnant women with non-HDP from October 2013 to June 2015 were included.The concentrations of 11 metals in maternal plasma samples were determined in Part 2.Modified poisson regression models were used to assess the association of single metal exposure with the risk of HDP.WQS regression model was used to investigate the impacts of mixed metal exposure on the risk of HDP,and to identify the metal with the largest contribution weight in the association.Elastic net(ENET)model was used to screen the impact of potential metals on HDP risk.RERI was calculated to evaluate the additive interaction effects between pre-pregnancy BMI and metal exposure in early pregnancy on HDP.(2)A nested case-control study was based on a prospective cohort to assess the mediation role of fatty acids in the associations of metal exposure with the developing HDP.A total of 92 HDP cases and 184 controls who had sufficient plasma samples in early pregnancy.The cases were randomly matched according to fetal sex and maternal age(± 1 year old)with the controls in plasma in early pregnancy were detected by gas chromatography-mass spectrometry.According to the above results that the five metals(Al,Cd,Pb,Hg,and Ni)with the largest weight in association with the risk of HDP and the high-risk blood trajectory.Multiple linear regression models were used to investigate the associations between metal exposure in early pregnancy and fatty acid levels in plasma.The conditional logistic regression model was used to assess the association between fatty acid in plasma during early pregnancy and the risk of HDP.Combined with the results above,we explored the mediating role of fatty acid in the association between metals and the risk of HDP.Results:(1)After adjusting for confounding factors,the results of modified poisson regression models showed that higher concentrations of Al,Cd,Pb,Ni,Hg,Ti,and Zn in plasma were significantly positively correlated with the risk of HDP.WQS regression model showed that the plasma concentration of metals mixture in the first trimester was positively associated with the risk of HDP(RR = 3.09,95% CI: 2.31,4.16,P < 0.05),among which Cd(31.6%),Al(22.4%),and Hg(20.4%)accounted for the largest weight..In the ENET model,we found that Al,Cd,Hg and Ni in plasma were positively correlated with the risk of HDP(β > 0).A positive additive interaction effects between higher pregnancy BMI and Al on the risk of HDP(RERI: 3.78,95% CI: 0.77,7.81).(2)Based on a nested case-control study,the same results from above that the higher concentrations of Al,Cd,Pb,Hg,and Ni in plasma were significantly positively associated with the risk of HDP.Multiple linear regression results showed higher Al levels were associated with decreased levels of C17:0and C18:1 n-7 and increased levels of C14:0 and C16:0.Higher Cd levels were associated with decreased levels of odd-chain saturated fatty acids,C15:0,and C17:0.Higher Hg levels were associated with increased levels of C14:0 and C18:3 n-3.Multinomial logistic regression models showed that higher levels of long-chain saturated fatty acids(LSFAs),C16:0,monounsaturated fatty acids(MUFAs),C16:1 n-7,and C18:1 n-9 in early pregnancy were significantly associated with the risk of HDP(P < 0.05).The levels of very-long-chain saturated fatty acids(VLSFAs),C20:0,C22:0,C24:0,Polyunsaturated fatty acids(PUFAs),n-6 PUFAs,n-3 PUFAs,C18:2 n-6,C20:2 n-6,and C22:4 n-6 in early pregnancy were significantly negatively associated with the risk of HDP(P < 0.05).We did not find evidence that the association of Al,Cd,Pb,Hg,and Ni exposure and risk of HDP was mediated through fatty acids.Conclusion: Mixed metal exposure in early pregnancy was significantly associated with an increased risk of HDP.The metals with greater weight include Cd,Pb,and Hg.Metal exposure in early pregnancy was associated with changes in plasma fatty acids levels in pregnant women.The levels of fatty acids subclasses(LSFAs,VLSFAs,MUFAs,PUFAs,n-3 PUFAs,and n-6 PUFAs)and fatty acids components(C16:0,C20:0,C22:0,C24:0,C16:1 n-7,C18:1 n-9,C18:2 n-6,C20:2 n-6,and C22:4 n-6)in plasma were associated with the risk of HDP. |
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