Association between phthalate exposure and blood pressure during pregnancy

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Association between phthalate exposure and blood pressure during pregnancy Xiaoyu Hana,b,1, Jiufeng Lic,1, Youjie Wanga,b,d, Shunqing Xua,b, Yuanyuan Lia,b, Hongxiu Liua,b, Yanqiu Zhouc, Hongzhi Zhaoc, Jing Fangc, Zongwei Caic,∗∗, Wei Xiaa,b,∗ a Key Laboratory of Environment and Health (HUST), Ministry of Education & Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Hubei, China b State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Hubei, China c State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China d Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China

A R T I C LE I N FO

A B S T R A C T

Keywords: Phthalates Blood pressure Pregnancy Fetus gender

Background: Phthalates are endocrine disrupting chemicals (EDCs) that pose a serious hazard to the human health. Many epidemiological studies revealed a relationship between phthalates exposure and blood pressure in general population, while the relationship in pregnant women remains unknown. Objectives: Aimed to elucidate whether phthalate exposure is associated with blood pressure among pregnant women. Methods: This study included 636 participants from Wuhan, China. Urine samples were conducted repeatedly in three trimesters, and 9 phthalates were measured in these samples. After each urine was sampled, all the participants completed blood pressure measurements. Associations between repeated measurements of phthalate concentration and blood pressure were evaluated by using generalized estimating equations. Stratified analysis by fetus gender was conducted. Results: Among the pregnant women with male fetuses, mono-i-butyl phthalate (MiBP) exposed in the 1st trimester was associated with the increased diastolic blood pressure (DBP) measured in the 2nd trimester, while the environmental risk score (ERS) measured in the 1st and 2nd trimester was positively associated with systolic blood pressure (SBP) and DBP in the 2nd trimester. No significant relationships were observed among all the population or pregnant women with female fetuses. Conclusions: Exposure to higher levels of MiBP may be related to increased blood pressure during pregnancy in pregnant women with male fetuses.

1. Introduction Phthalates are endocrine disrupting chemicals (EDCs). As good plasticizers and solvents, phthalates are generally applied to the production of industry and personal-care. Phthalates with high molecular weight (HMW) (> 250 g/mol), such as di(2-ethylhexyl) phthalate (DEHP), are mainly used in polyvinyl chloride plastics polymer and plastisol applications, including clothing, toys and food packaging. While phthalates with low molecular weight (LMW) (< 250 g/mol), such as diethyl phthalate (DEP) and di-n-butyl phthalate (DnBP), are

applied to pharmaceuticals, cosmetic and insecticide (De Toni et al., 2017; Koniecki et al., 2011; Schettler, 2006; Wittassek et al., 2011). People can be exposed to phthalates in a variety of ways: diet (foods and water contaminated with plastic containers), breathing (air, dust, fragrance) and dermal absorption (creams, moisturizers, shampoos) (Giovanoulis et al., 2018; Huang et al., 2018; Varshavsky et al., 2018). Previous studies have shown that phthalates are harmful to the human health. Exposure to phthalates has been reported to be associated with obesity, asthma, neurodevelopmental defect, endometriosis, infertility and testicular cancer (Bekö et al., 2013; Du et al., 2016; Sharpe and

∗

Corresponding author. School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Corresponding author. Department of Chemistry, Hong Kong Baptist University, Hong Kong, China. E-mail addresses: [email protected] (Z. Cai), [email protected] (W. Xia). 1 Both the authors contributed equal to the article. ∗∗

https://doi.org/10.1016/j.ecoenv.2019.109944 Received 28 March 2019; Received in revised form 8 November 2019; Accepted 9 November 2019 0147-6513/ © 2019 Elsevier Inc. All rights reserved.

Please cite this article as: Xiaoyu Han, et al., Ecotoxicology and Environmental Safety, https://doi.org/10.1016/j.ecoenv.2019.109944

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2.2. Urine sampling and measuring

Skakkebaek, 2008; Upson et al., 2013). According to the World Health Organization (WHO), hypertension was the biggest contributor of global burden of disease and global mortality (Lim et al., 2012; Poulter et al., 2015). It is related to obesity, insulin resistance and increased levels of circulating angiotensin II, which may induce cardiovascular disease (Perkins et al., 2016; Stea et al., 2014). There are significant hemodynamic and structural changes in the cardiovascular and hematological system in pregnant women, such as expanded blood volume, increased heart rate and decreased platelet count (Hill and Pickinpaugh, 2008; Jafar et al., 2018), so the pregnant women are at higher risk of hypertension than general population. Studies have shown that pregnant women with increments of blood pressure, even without hypertension, may more prone to abnormal pregnancy results, including fetal growth restriction, preterm birth and perinatal deaths (Bakker et al., 2011; Macdonald-Wallis et al., 2014; Steer et al., 2004; Zhang et al., 2007). In addition, the increments in pregnancy blood pressure may result in long-lasting effects, such as later hypertension and offspring obesity (Dunietz et al., 2017; Zheng et al., 2017). Studies on the relationship of phthalate exposure with blood pressure among pregnant women are limited. Werner et al.‘s study revealed that maternal urinary mono-benzyl phthalate (MBzP) measured at 16 gestational weeks was significantly related to increased DBP measured before 20 weeks (Werner et al., 2015). Another study by Warembourg et al. measured urinary phthalates and blood pressures in the second and third trimester and found that urinary phthalates exposed in the second trimester were negatively related to blood pressure (Warembourg et al., 2018). Philips et al.‘s study investigated the relationship between spot urinary phthalates measured in the first trimester and repeated blood pressures in three trimesters and found no relationship (Philips et al., 2019). The difference in exposure levels and study designs may lead to the different results. Furthermore, these previous studies didn't measure phthalate exposure and blood pressure through the whole pregnancy which may not able to identify the sensitive exposure window. In the present study, to explore the correlations between phthalate exposure and blood pressure, we carried out repeated measures of urinary phthalate metabolites and blood pressure in the first, second and third trimester to cover the whole pregnancy. Further stratified analyses were conducted because studies have shown that maternal blood pressure may vary between the different fetus gender (Al-Qaraghouli and Fang, 2017; Brown, 2016).

Each pregnant woman provided urinary samples in the first trimester (13.31 ± 2.13 week), second trimester (24.13 ± 3.69 week) and third trimester (36.22 ± 3.16 week), respectively. When these participants took a prenatal examination at the study hospital, we gave them a 50 mL polypropylene container to collect spot urine. These samples were kept at 4 °C immediately and transferred into 5 mL polypropylene tubes within 12 h and stored at −20 °C in Tongji Medical College until analysis. We measured nine phthalate metabolites in this study, including mono-methyl phthalate (MMP), mono-ethyl phthalate (MEP), mono-i-butyl Phthalate (MiBP), mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP). The detailed procedures of SPE-UPLC–MS/MS method for phthalate measurement were introduced in a previous study (Zhu et al., 2016). In brief, urinary samples were hydrolyzed with β-glucuronidase, and then loaded onto the solid phase extraction cartridges. After the extraction, rinse and elution were performed. The eluents were dried and then dissolved in 500 μL acetonitrile/water (1:9, v/v). Finally, the Acquity TQD mass spectrometer coupled with the Acquity UPLC system were used to measure the concentration of phthalates. In each batch of measurements, we also included standard samples and blank samples to correct the deviation and ensure the accuracy of the results. The limit of detection (LOD) of nine phthalate metabolites ranged between 0.05 ng/ mL and 0.2 ng/mL. The range of the recovery were from 80.0 ± 7.2% to 127.1 ± 1.4%. To adjust the variation of urinary dilution, the specific gravity (SG) of each urinary samples were measured using a hand-held digital refractometer (Atago PAL-10S, Atago, Japan). 2.3. Data collection The basic information of each participant was obtained through questionnaires conducted by well-trained nurses when the participants were admitted to hospital for labor. The interviewers carried out the face-to-face interviews to collect the information on demographic characteristics, socioeconomic data and lifestyle, including age, occupation, education, household income, physical activity, alcohol consumption (drunk alcohol beverages during pregnancy), active smoking (pregnant women smoked tobacco at least once throughout pregnancy) and passive smoking (nonsmoking women living in an apartment or workplace with tobacco smoke during pregnancy). Other information, including height, weight before pregnancy and at delivery, parity, last menstrual period, gestational disease (e.g. gestational diabetes mellitus (GDM), hypertension) and fetus gender, were extracted from medical records. The pre-pregnancy body mass index (BMI) was calculated using the following equation: pre-pregnancy BMI = pre-pregnancy weight (kilogram, kg)/height2 (meter, m). The gestational weight gain (GWG) was calculated by weight at delivery subtract pre-pregnancy weight. The diagnostic criteria for GDM were in accordance with the recommendations of IADPSG (International Association of et al., 2010). An automated sphygmomanometer (A&D TM-2655) (Kobalava et al., 2006) was used to measure blood pressure and it was regularly examined and repaired. Before measurements, participants were required to rest for at least 5 min and then blood pressure was measured with an upright position. The measurements of blood pressure were conducted by nurses using standard procedure. SBP and DBP were measured twice over a 1-min interval if the first measurement was above the normotensive level, and the mean value of the two measurements was recorded. We selected the blood pressure values closest to the time of urine collection for analysis (the mean ± SD of time interval was 3.47 ± 11.95 day), for phthalates can be metabolized and eliminated from the body within hours of exposure. According to the

2. Methods 2.1. Participants The participants were from a prospective birth cohort study in Wuhan, China. Pregnant women who met the inclusion criteria were enrolled in the birth cohort when they went to the Wuhan Women and Children Medical Care Center for their first antenatal care. The inclusion criteria were: (1) gestational age was less than 16 weeks; (2) had a singleton; (3) had resided in Wuhan for more than 1 year and didn't plan to move out in the foreseeable future; (4) planned to take obstetric examination and delivery at this study hospital; (5) agreed to provide urine samples at the prenatal examinations during pregnancy. All participants signed informed consent, and the committee of Tongji Medical College approved the protocol of this study. Between September 2013 and March 2015, a total of 846 pregnant women were recruited and 636 participants provided a complete serial spot urine samples and completed blood pressures in each of the three trimesters. We excluded people whose urine gravity was 1 (n = 3), which may reflect an abnormal urinary excretion. This exclusion result in 633 participants for analysis.

2

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between phthalates exposure and blood pressure. In order to avoid multicollinearity issues incurred by the inclusion of all 7 phthalates, we examined the correlation structure of them (7 phthalates) (Table S3). MECPP, MEHHP and MEOHP showed strong correlation (greater than 0.5), and among them, we chose MEHHP that showed the significant association with blood pressure. Therefore, MEP、MiBP、MnBP、 MEHP and MEHHP were selected to construct the ERS. As fetus gender may affect blood pressure (Al-Qaraghouli and Fang, 2017; Brown, 2016), we also conducted a stratified analysis in all models, to explore the possible modification effect of fetus gender. In this study, the phthalate metabolites with a detection rate less than 50% were excluded from the analysis and the concentrations of urinary phthalate metabolites, which were below LOD, were replaced by LOD/√2. Even so, there can be biases (Dinse et al., 2014). Therefore, we conducted sensitivity analysis using multiple imputation method based on Markov Chain Monte Carlo (MCMC) method to see if findings are robust (Bernhardt et al., 2015). Besides, considering that the large span of collection time between urine sample and blood pressure (the mean ± SD of time interval was 3.47 ± 11.95 day), participants who provided the two values on the same day were selected as a subgroup for another sensitivity analysis. In the final adjusted models, we adjusted for pre-pregnancy BMI (kg/m2), household income (< 100,000 or ≥100,000 yuan/year), GDM (yes or no) and fetus gender (male or female) because these confounders changed the main effect by more than 10% in our analysis, and we also adjusted for maternal age (years) and parity (nulliparous or multiparous) because they were reported to affect blood pressure in previous studies (Okonofua et al., 1992; Parikh et al., 2017). In the stratified analyses, all these covariates were used to correct models except fetus gender. The statistical analyses in this study were completed by Statistical Analysis System (SAS) (version 9.4). All tests were bilateral and the α was 0.05.

guidelines for diagnosis and treatment of hypertension during pregnancy in China (Chinese society of., 2015), pregnant women with SBP≥130 mmHg and (or) DBP≥80 mmHg are at high risk of related diseases. Besides, our recently published study showed that adopting the 2017 ACC/AHA high blood pressure guideline (Whelton et al., 2018) may improve the detection of high blood pressure during pregnancy and the efforts to reduce maternal and neonatal risk in Chinese pregnant women (Hu et al., 2019). Therefore, we used the classification criteria suggested by this guideline in this study (defined hypertension as SBP≥130 mmHg and (or) DBP≥80 mmHg over pregnancy). 2.4. Statistical analyses The concentrations of urinary phthalate metabolites, which were below LOD, were replaced by LOQ/√2 (Hornung and Reed, 1990). We corrected the concentrations of all the samples by its SG using the formula: Pc = Pi[(1.012–1)/(SGi-1)]. Pc was the SG-adjusted concentration of the sample (ng/mL), Pi was the measured concentration of the sample (ng/mL), SGi was the specific gravity of the sample and 1.012 was the median value of the specific gravity of all the samples in this study. In consideration of the similar exposure routes and structures, we calculated the molar concentration of DEHP (a high molecular phthalate) and LMW phthalates (Benjamin et al., 2017). ΣDEHP was the molar sum of MEHP (278 g/mol), MEOHP (292 g/mol), MEHHP (294 g/ mol), and MECPP (308 g/mol)). ΣLMW was the molar sum of MEP (194 g/mol), MiBP (222 g/mol), and MnBP (222 g/mol). MMP and MBzP were also excluded from analysis due to low detection rates (below 50%). All the concentrations of metabolites showed a skewed distribution, so we did a natural logarithm (ln) transformation to obtain the normal distribution for analyzing. The mixed linear model with random intercept-only was applied to calculate the intraclass correlation coefficients (ICC) for phthalate metabolites measured in each trimester. Linear regression models were applied to estimate the relationship of phthalate exposure with blood pressure (SBP and DBP, respectively) measured in the first trimester. To examine the relationship with blood pressure prospectively, we evaluated the association between exposure measured in the first and second trimester and blood pressure measured in the second trimester, as well as the association between exposure measured in three trimesters and blood pressure measured in the third trimester. To allowing for the autocorrelation of trimester measurements of phthalates in the same individual, we performed a generalized estimating equation model, using independent correlation structure, with a multiplicative interaction term between trimester and ln-transformed phthalate metabolites concentrations to estimate the associations of trimester-specific exposures with blood pressure (Sanchez et al., 2011). In the methods, two or three trimester urinary concentrations of the same individual were simultaneously adjusted, which were helpful to correct the autocorrelation. The results of analyses were described by coefficients (βs) and 95% confidence intervals (CIs). We also examined the relationship between average concentration (geometric mean) of phthalates measured in the first and second trimesters and blood pressure in the second trimester, as well as the average concentration during the whole pregnancy and blood pressure in the third trimester. These were implemented by multiple linear regression models. Considering of the risk of false positive findings due to multiple testing comparisons, we used false discovery rate (FDR) to correct the P values to adjust for multiple testing, and calculated the FDR-adjusted Pvalues (P-FDR) by the available spreadsheet software developed by Pike, (2011). In addition to analyzing each compound separately, we construct an aggregate summary of total phthalate exposure (the environmental risk score, ERS) to explore the combined effects of multiple pollutants (Woythaler et al., 2011). ERS is the linear combination of selected phthalates, which were weighted by their associated regression coefficients in the adjusted models used for estimating the association

3. Results 3.1. Characteristics of participants Table 1 shows the general characteristics of participants in this study. The average age of participating women at delivery was 28.6 ± 3.3 (mean ± SD) years old. Most of them (79.3%) had college education and more than 40% people had a household income ≥100 thousands yuan. The mean ( ± SD) pre-pregnancy BMI of them was 20.8 ( ± 2.8) kg/m2, and the average gestational weight gain was 16.5( ± 4.4) kg. About 85% of these pregnant women were nulliparous. No participants reported drinking alcohol and only on person smoked during pregnancy, but nearly 40% participants were passively exposed to cigarettes smoke. About 77.2% participants took exercise every day. Among the women, 7.9% were diagnosed with GDM and 7.4% were diagnosed with hypertension using the 2017 ACC/AHA criteria. The women who gave birth to a boy were account for 52.1%. We compared the basic information between recruited women (n = 846) and included women (n = 633) in the present study, and found all characteristics weren't statistically varied between the two groups. 3.2. Maternal urinary concentrations of phthalates Table 2 shows the detection rates and distributions of nine urinary phthalate metabolites as well as ΣDEHP and ΣLMW. The detection rate for MMP and MBzP was less than 50%, and the detection rate for the other metabolite was over 85%. The GMs of these phthalates ranged from 3.25 ng/mL to 42.97 ng/mL in the first trimester, 3.01 ng/mL to 29.36 ng/mL in the second trimester, and 3.20 ng/mL to 55.63 ng/mL in the third trimester. The concentration of LMW phthalates was higher than the metabolites of DEHP in each trimester, with a descending order of the average concentrations (GMs) over pregnancy as following: 3

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3.3. Trimester-specific maternal phthalates exposure and blood pressure

Table 1 Characteristics of participants in this study (n = 633). Characteristic

N(%) or Mean ± SD

Maternal age at delivery (years) Maternal education junior school or less high school completed college Household income(RMB) < 100,000 ≥100,000 Missing Pre-pregnancy BMI(kg/m2) Gestational weight gain(kg) Gestational diabetes mellitus no yes Parity nulliparous multiparous Passive smoking no yes Physical activity low (not active) medium high (active every day) Missing fetus gender male female Hypertension no yes

Tables 3–5 show the relationships of phthalate exposure with blood pressure measured in the first, second and third trimester, respectively. For overall population, no relationship was observed between phthalates exposure in the first trimester and blood pressure measured in the first trimester (Table 3). When stratified by fetus sex, the concentrations of MEHHP (adjusted β = 1.35, 95% CI: 0.02, 2.68), MEOHP (adjusted β = 1.45, 95% CI: 0.13, 2.76) and ERS (adjusted β = 0.91, 95% CI: 0.06, 1.76) were associated with increased SBP in women with female fetuses, although these associations were not significant (PFDR > 0.05). When the relationship of phthalate exposure in the first and second trimester and blood pressure measured in the second trimester was analyzed (Table 4), the only significant associations were occurred among women carrying male fetuses. In women with male fetuses, DBP measured in the second trimester was positively related to MiBP (adjusted β = 0.76, 95% CI: 0.24, 1.28, P-FDR = 0.05) and ΣLMW (adjusted β = 1.07, 95%CI: 0.30, 1.83, P-FDR = 0.05) in the first trimester. ERS in the first (adjusted β = 0.53, 95% CI: 0.16, 0.90, PFDR = 0.05) and the second trimester (adjusted β = 1.13, 95% CI: 0.24, 2.03, P-FDR = 0.05) were both related to increased DBP in the second trimester. Besides, ΣLMW (adjusted β = 0.92, 95% CI: 0.00, 1.84, P-FDR = 0.28) and ERS (adjusted β = 0.85, 95% CI: 0.25, 1.44, PFDR = 0.18) in the first trimester were also positively associated with SBP among women carrying male fetuses, although the associations were not statistically significant based on the P-FDR. We didn't find significant associations of phthalates exposed in the three trimesters with blood pressure in the third trimester (Table 5). But in women with male fetuses, MiBP (adjusted β = 0.55, 95% CI: 0.01, 0.10, P-FDR = 0.24), MnBP (adjusted β = 0.68, 95% CI: 0.08, 1.29, PFDR = 0.23), ΣLMW (adjusted β = 0.88, 95% CI: 0.08, 1.69, PFDR = 0.23) and ERS (adjusted β = 0.57, 95% CI: 0.11, 1.03, PFDR = 0.23) in the first trimester tended to be positively correlated to DBP in the third trimester, though the estimation didn't reach statistical significance.

P

included (n = 633)

recruited (n = 846)

28.6 ± 3.3

28.6 ± 3.3

35(5.5) 96(15.2) 502(79.3)

49(5.8) 134(15.8) 663(78.4)

124(57.2) 270(42.6) 1(0.2) 20.8 ± 2.8 16.5 ± 4.4

485(57.3) 358(42.3) 3(0.4) 20.9 ± 2.9 16.5 ± 4.6

583(92.1) 50(7.9)

780(92.2) 66(7.8)

538(85.0) 95(15.0)

728(86.1) 118(13.9)

393(62.1) 240(37.9)

562(66.4) 284(33.6)

48(7.6) 89(14.1) 489(77.2) 7(1.1)

69(8.2) 129(15.2) 641(75.8) 7(0.8)

330(52.1) 303(47.9)

443(52.4) 403(47.6)

0.91 0.91

0.77

0.42 0.76 0.95

0.57

0.08

0.83

0.93

524(82.8) 109(17.2)

Abbreviations: SD, standard deviation; pre-pregnancy BMI, pre-maternal body mass index.

MnBP (66.68 ng/mL), MiBP (16.09 ng/mL), MEP (13.54 ng/mL), MECPP (11.46 ng/mL), MEHHP (7.29 ng/mL), MEOHP (5.76 ng/mL) and MEHP (4.99 ng/mL) (data was shown in Table S1). The intraclass correlation coefficient (ICC) of each metabolite was greater than 0 and less than 0.5.

3.4. Averaged maternal phthalates exposure and blood pressure The associations of averaged maternal phthalates exposure with blood pressure are shown in Tables 6 and 7. The average concentrations of all these chemicals were not significantly associated with SBP or DBP in the second and the third trimester. The results of stratified analysis by fetus gender also tend to be null. In the sensitivity analysis using multiple imputation method, similar

Table 2 The distribution of urinary phthalate metabolite concentrations (SG-adjusted, ng/mL) in three trimesters respectively. Compounds (ng/mL)

MMP MEP MiBP MnBP MBzP MEHP MEOHP MEHHP MECPP ΣDEHPa ΣLMWa

LOD

0.20 0.10 0.10 0.10 0.10 0.10 0.05 0.05 0.01 – –

1st trimester

2nd trimester

3rd trimester

ICC

Detection rate (%)

GM

Percentile (25th,50th,75th)

Detection rate (%)

GM

Percentile(25th,50th,75th)

Detection rate (%)

GM

Percentile(25th,50th,75th)

36.48 98.27 93.08 97.80 45.75 90.72 99.69 99.69 99.69 – –

NA 11.12 11.83 42.97 NA 3.25 4.80 6.43 9.70 107.28 409.90

NA,NA,5.89 5.2,10.45,23.74 7.74,15.84,31.14 19.75,44.34,110.07 NA,NA,0.23 1.41,3.36,7.38 2.72,4.63,8.38 3.4,6.13,11.14 5.7,9.2,16.31 62.41,100.19,174.21 207.6407.51,861.84

31.92 98.58 89.47 96.07 30.03 87.89 99.69 99.69 99.84 – –

NA 9.09 7.99 29.36 NA 3.01 4.00 4.95 8.47 88.65 311.24

NA,NA,7.73 4.03,8.1,13.18 4.8,11.31,22.49 13.55,33.53,78.76 NA,NA,0.21 1.33,3.13,7.82 1.96,4.08,6.69 2.47,4.81,8.35 4.81,8.04,13.18 46.37,84.08,136.50 151.53,301.09,643.54

36.01 99.21 90.57 97.96 37.74 85.06 99.84 99.84 99.69 – –

NA 10.32 11.65 55.63 NA 3.20 5.10 6.16 10.02 108.01 485.38

NA,NA,8.63 4.86,9.8,22.37 7.44,16.05,31.41 25.91,58.34,150.65 NA,NA,0.22 1.41,3.44,8.04 3.11,5.07,8.12 3.53,6.24,10.06 6.25,10.17,16.02 63.99,104.18,165.59 244.24,496.58,1011.38

Abbreviations: SG, specific gravity; GM, geometric mean; LOD, limit of detection; NA, not available; ICC, intraclass correlation coefficient. ΣDEHP: the molar sum of MEHP (292 g/mol), MEOHP (292 g/mol), MEHHP (294 g/mol), and MECPP (308 g/mol). ΣLMW: the molar sum of MEP (194 g/mol), MiBP (222 g/mol), and MnBP (222 g/mol). a The unit is nmol/L. 4

0.05 0.24 0.17 0.08 0.11 0.17 0.49 0.11 0.33 0.32 0.08

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0.24(-0.60,1.08) −0.48(-1.20,0.24) 0.02(-0.72,0.77) −0.19(-1.23,0.85) 0.04(-0.70,0.77) 0.88(-0.28,2.04) 1.07(-0.01,2.14) 1.03(-0.04,2.10) 0.92(-0.21,2.05) 1.23(0.33,2.12)

adjusted β (95% CI)

d

0.71 0.71 0.97 0.13 0.71 0.15 0.18 0.71 0.13 0.13

P- FDR

4. Discussion

−0.27(-1.31,0.77) −0.02(-0.91,0.88) −0.22(-1.14,0.70) −0.50(-1.78,0.78) 0.28(-0.62,1.18) 1.25(-0.18,2.68) 1.35(0.02,2.68) 1.45(0.13,2.76) 1.32(-0.08,2.71) 0.91(0.06,1.76)

adjusted β (95% CI)

SBP

c

In this prospective cohort study, we didn't find evident associations of phthalate exposure with blood pressure in pregnant women, except that maternal urinary phthalates exposed in the first trimester were positively associated with blood pressure in the second trimester among women with male fetuses. To the best of our knowledge, this is the first study examining the trimester-specific association of urinary phthalates and blood pressure during pregnancy. There are three reports that have addressed the same research question with us. They all repeatedly collected samples based on prospective cohorts, but selected different models for analysis. In this study, we found that urinary MiBP in the first trimester were positively related to blood pressure in the second trimester. Werner at al. reported that maternal urinary MBzP measured at 16 gestational weeks was significantly related to higher DBP measured before 20 weeks (Werner et al., 2015), and found no associations between other phthalates and blood pressure. Compared to the detection rate of MBzP in Werner et al.‘s study (> 75%), our population had much lower detection rate of that (< 50%). MBzP was excluded from analysis in our study. In addition, the authors used linear regression models to estimate the association between phthalates and blood pressure in different trimesters, which may ignore the autocorrelation of trimester measurements of phthalates in the same individual. In another study by Philips et al., they measured phthalate exposure in the first trimester and repeated blood pressure in three trimesters. Repeated measurement regressions were used to estimate the associations and the results were null (Philips et al., 2019). Philips et al.‘s study used urinary samples in the first trimester and the trajectory of blood pressure for analysis, which may not be able to identify the specific-trimester association, though their population has higher unadjusted urinary MiBP concentrations than the present study (median ng/mL: 20.69 vs. 10.23). Another study conducted by Warembourg et al. reported negative relationships of MiBP in the second trimester with blood pressure in the second and third trimester (Warembourg et al., 2018), while we didn't observe these relationships in our study. Using the linear regression models to estimate the association which may ignore the autocorrelation of phthalates may cause the difference. Besides, the discrepancy in these findings may be attributed to different exposure levels, study designs, diverse race, region, living habits, care products usage and other conditions. When comparing the effects of multi-phthalates risk score to single phthalate, we found that ERS in the first and second trimester may also related to the SBP in the second trimester in comparison to MiBP, although not statistically significant based on the P-FDR. This may indicate that mixtures of multiple pollutants are more harmful to human health. Meanwhile, the effect on blood pressure disappeared when the concentration of phthalates were averaged. Therefore, it is of great significance to estimate the trimester-specific association of phthalates exposure with blood pressure. Although the phthalates-related changes in blood pressure were only 0.76–1.13 mm Hg in present study, increased blood pressure during pregnancy may lead to preterm birth, later hypertension and other health consequences, future researches with large sample should be carried out to confirm the relation of phthalate exposure with blood pressure and risk of hypertension during pregnancy.

0.95 0.97 0.97 0.95 0.97 0.95 0.95 0.95 0.97 0.95 −0.36(-1.24,0.52) 0.06(-0.62,0.73) 0.02(-0.73,0.77) 0.29(-0.70,1.27) −0.08(-0.92,0.76) −0.95(-2.17,0.27) −0.44(-1.68,0.81) −0.77(-2.01,0.47) 0.14(-1.26,1.54) 0.94(-0.81,2.69)

c

adjusted β (95% CI)

1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 0.01(-0.53,0.55) −0.16(-0.59,0.27) 0.00(-0.46,0.47) 0.07(-0.55,0.70) −0.14(-0.63,0.35) −0.10(-0.85,0.64) 0.16(-0.57,0.89) 0.12(-0.61,0.84) 0.27(-0.52,1.06) 1.55(-0.85,3.95)

b

adjusted β (95% CI)

DBP d

−0.34(-1.01,0.33) 0.06(-0.48,0.59) −0.05(-0.63,0.54) 0.04(-0.74,0.82) 0.03(-0.58,0.64) −0.06(-0.99,0.88) 0.36(-0.55,1.27) 0.24(-0.67,1.14) 0.68(-0.31,1.66) 1.10(-0.49,2.68) MEP MiBP MnBP ΣLMWa MEHP MECPP MEHHP MEOHP ΣDEHPa ERS

adjusted β (95% CI)

b

0.92 0.92 0.92 0.92 0.92 0.92 0.92 0.92 0.90 0.90

P- FDR SBP

Abbreviations: CI, confidence interval. ΣDEHP: the molar sum of MEHP (292 g/mol), MEOHP (292 g/mol), MEHHP (294 g/mol), and MECPP (308 g/mol). ΣLMW: the molar sum of MEP (194 g/mol), MiBP (222 g/mol), and MnBP (222 g/mol). a The unit is nmol/L. b Adjusted for gestational age, household income, pre-pregnancy BMI, gestational diabetes mellitus, parity, fetus gender. c Adjusted for gestational age, household income, pre-pregnancy BMI, gestational diabetes mellitus, parity. d P values for estimating false-discovery rate (FDR) to correct multiple comparisons.

−0.12(-0.81,0.58) 0.03(-0.50,0.56) −0.04(-0.63,0.55) 0.19(-0.59,0.97) −0.25(-0.91,0.41) −0.80(-1.76,0.16) −0.62(-1.59,0.36) −0.67(-1.65,0.30) −0.36(-1.46,0.74) 0.67(-0.41,1.75)

adjusted β (95% CI)

DBP d

P-FDR SBP P- FDR

d

Women with male fetus (n = 330) All participants (n = 633) Chemicals (ng/L)

Table 3 Associations between ln-transformed urinary phthalate metabolite concentrations (SG-adjusted) and blood pressure in the 1st trimester.

c

0.91 0.91 0.91 0.91 0.87 0.55 0.55 0.55 0.87 0.55

P- FDR

d

Women with female fetus (n = 303)

DBP

c

0.90 0.95 0.95 0.20 0.32 0.28 0.28 0.81 0.10 0.20

P- FDR

d

results were observed between MiBP (adjusted β = 1.24, 95% CI: 0.24, 2.23), ΣLMW (adjusted β = 0.61, 95% CI: −0.26, 1.47) and ERS (adjusted β = 0.54, 95% CI: 0.19, 0.90) in the first trimester and DBP measured in the second trimester among women with male fetuses. When we restricted analyses in the subgroup who had blood pressure measurement and urine collected on the same day, positive associations of MiBP, ΣLMW and ERS in the first trimester with DBP measured in the second trimester were also found among women with male fetuses, but they were not statistically significant. Data was shown in supplemental materials (Tables S4–S11).

5

6

0.91 0.91

0.91 0.91

0.60 0.60

−0.25(-1.08,0.59) 0.08(-0.69,0.86)

−0.17(-1.08,0.74) 0.09(-0.73,0.90)

0.82(0.02,1.62) 0.78(-0.33,1.90)

0.91 0.91

−0.30(-0.87,0.26) −0.10(-0.65,0.44)

0.91 0.91

0.60 0.91

0.65(-0.07,1.38) 0.35(-0.33,1.04)

−0.17(-1.01,0.66) 0.21(-0.57,1.00)

0.60 0.91

0.47(-0.07,1.00) 0.08(-0.40,0.56)

0.91 0.98

0.91 0.68

0.21(-0.29,0.70) 0.31(-0.14,0.76)

−0.31(-1.17,0.55) −0.01(-0.83,0.80)

0.91 0.91

b

P- FDR

0.09(-0.53,0.71) 0.06(-0.58,0.69)

adjusted β (95% CI)

SBP

All participants (n = 633) d

0.47(-0.10,1.05) 0.75(-0.24,1.75)

0.72(-0.08,1.51) −0.27(-0.98,0.44)

0.49(-0.24,1.22) −0.20(-0.87,0.48)

0.42(-0.31,1.15) −0.09(-0.78,0.60)

0.42(-0.33,1.17) −0.29(-1.00,0.42)

0.16(-0.34,0.65) −0.08(-0.56,0.39)

0.52(-0.11,1.16) −0.18(-0.78,0.42)

0.30(-0.17,0.77) −0.32(-0.74,0.09)

0.26(-0.17,0.69) −0.10(-0.49,0.29)

0.25(-0.29,0.79) 0.13(-0.42,0.68)

adjusted β (95% CI)

DBP b

0.56 0.56

0.56 0.71

0.56 0.71

0.56 0.80

0.56 0.71

0.71 0.78

0.56 0.71

0.56 0.56

0.56 0.71

0.67 0.71

P- FDR

d

0.85(0.25,1.44) 1.03(0.17,1.89)

−0.73(-2.04,0.59) −0.27(-1.34,0.79)

−1.04(-2.21,0.12) −0.25(-1.26,0.76)

−0.94(-2.11,0.22) −0.10(-1.15,0.94)

−0.87(-2.02,0.27) −0.38(-1.45,0.69)

−0.50(-1.29,0.28) −0.42(-1.14,0.30)

0.92(0.00,1.84) 0.78(-0.17,1.73)

0.53(-0.17,1.23) 0.11(-0.57,0.80)

0.54(-0.09,1.17) 0.55(-0.05,1.15)

0.10(-0.73,0.92) 0.35(-0.54,1.25)

adjusted β (95% CI)

SBP c

0.18 0.20

0.43 0.73

0.28 0.73

0.28 0.84

0.28 0.65

0.38 0.43

0.28 0.28

0.28 0.83

0.28 0.28

0.84 0.63

P- FDR

d

Women with male fetus (n = 330)

0.20 0.35 0.05 0.05

0.53(0.16,0.90) * 1.13(0.24,2.03) *

0.43 0.38

0.53 0.43

0.46 0.35

1.06(-0.02,2.15) −0.68(-1.56,0.20)

0.51(-0.46,1.48) −0.50(-1.34,0.34)

0.37(-0.60,1.34) −0.44(-1.30,0.43)

0.43(-0.52,1.39) −0.64(-1.53,0.25)

0.84 0.35

0.05 0.93

1.07(0.30,1.83) * 0.03(-0.75,0.82) 0.10(-0.55,0.75) −0.45(-1.04,0.15)

0.16 0.38

0.05 0.93

0.76(0.24,1.28) * 0.04(-0.46,0.54) 0.60(0.01,1.18) −0.33(-0.9,0.23)

0.35 0.35

c

P- FDR

0.46(-0.23,1.14) 0.50(-0.24,1.24)

adjusted β (95% CI)

DBP

Abbreviations: CI, confidence interval. ΣDEHP: the molar sum of MEHP (292 g/mol), MEOHP (292 g/mol), MEHHP (294 g/mol), and MECPP (308 g/mol). ΣLMW: the molar sum of MEP (194 g/mol), MiBP (222 g/mol), and MnBP (222 g/mol). *P < 0.05. a The unit is nmol/L. b Adjusted for gestational age, household income, pre-pregnancy BMI, gestational diabetes mellitus, parity, fetus gender. c Adjusted for gestational age, household income, pre-pregnancy BMI, gestational diabetes mellitus, parity. d P values for estimating false-discovery rate (FDR) to correct multiple comparisons.

MEP 1st trimester 2nd trimester MiBP 1st trimester 2nd trimester MnBP 1st trimester 2nd trimester ΣLMWa 1st trimester 2nd trimester MEHP 1st trimester 2nd trimester MECPP 1st trimester 2nd trimester MEHHP 1st trimester 2nd trimester MEOHP 1st trimester 2nd trimester ΣDEHPa 1st trimester 2nd trimester ERS 1st trimester 2nd trimester

Chemicals (ng/L)

Table 4 Associations between ln-transformed urinary phthalate metabolite concentrations (SG-adjusted) and blood pressure in the 2nd trimester.

d

1.27(0.13,2.42) 0.79(-0.37,1.95)

0.49(-0.77,1.76) 0.61(-0.66,1.88)

0.70(-0.50,1.90) 0.55(-0.67,1.76)

0.77(-0.44,1.98) 0.64(-0.56,1.85)

0.53(-0.77,1.83) 0.48(-0.78,1.75)

0.00(-0.82,0.82) 0.38(-0.47,1.22)

0.15(-1.02,1.32) −0.12(-1.12,0.87)

0.60 0.96

0.69 0.69

0.69 0.69

0.69 0.69

0.69 0.69

1.00 0.69

0.96 0.96

0.69 0.98

0.69 1.00

−0.49(-1.30,0.32) −0.01(-0.69,0.67) 0.35(-0.49,1.19) 0.05(-0.62,0.72)

0.96 0.79

c

P- FDR

0.11(-0.84,1.05) −0.27(-1.17,0.62)

adjusted β (95% CI)

SBP

d

Women with female fetus (n = 303)

1.03(0.01,2.04) 1.07(0.03,2.11)

0.38(-0.79,1.55) 0.40(-0.77,1.57)

0.46(-0.64,1.57) 0.28(-0.84,1.40)

0.46(-0.65,1.57) 0.41(-0.70,1.52)

0.39(-0.81,1.59) 0.25(-0.91,1.42)

0.50 0.69

0.69 0.69

0.69 0.73

0.69 0.69

0.69 0.74

0.69 0.69

0.69 0.69

−0.39(-1.46,0.68) −0.33(-1.24,0.59) 0.25(-0.50,1.00) 0.50(-0.27,1.28)

0.76 0.69

−0.14(-0.91,0.63) −0.25(-0.87,0.37)

0.97 0.70 0.69 0.69

c

P- FDR

−0.61(-1.35,0.14) −0.25(-0.87,0.38)

0.02(-0.85,0.89) −0.25(-1.07,0.58)

adjusted β (95% CI)

DBP

d

X. Han, et al.

Ecotoxicology and Environmental Safety xxx (xxxx) xxxx

7

0.95 0.95 0.97

0.95 0.72 0.95

0.68 0.53 0.30

−0.11(-0.98,0.77) 0.10(-0.72,0.91) −0.07(-0.99,0.86)

0.15(-0.80,1.11) 0.42(-0.44,1.28) −0.17(-1.18,0.83)

0.53(-0.19,1.24) 0.60(-0.02,1.23) 0.96(0.31,1.61)

0.95 0.80 0.68

0.07(-0.52,0.66) 0.21(-0.36,0.79) −0.34(-0.90,0.21)

0.68 0.72 0.95

0.68 0.80 0.68

0.50(-0.26,1.26) 0.26(-0.46,0.98) 0.46(-0.30,1.21)

0.52(-0.36,1.40) 0.39(-0.44,1.21) 0.11(-0.85,1.07)

0.68 0.97 0.68

0.40(-0.16,0.97) −0.02(-0.52,0.48) 0.31(-0.24,0.87)

0.72 0.85 0.97

0.80 0.53 0.97

0.20(-0.32,0.72) 0.43(-0.04,0.90) −0.03(-0.52,0.47)

−0.43(-1.33,0.48) −0.27(-1.13,0.59) −0.02(-0.92,0.88)

0.95 0.68 0.30

b

P- FDR

0.08(-0.57,0.73) 0.40(-0.26,1.06) 0.84(0.16,1.51)

adjusted β (95% CI)

SBP

All participants (n = 633) d

0.57(0.14,0.99) 1.04(-0.26,2.34) 1.40(0.38,2.42)

0.32(-0.45,1.09) 0.35(-0.34,1.04) 0.05(-0.76,0.86)

0.14(-0.57,0.84) 0.12(-0.53,0.78) −0.1(-0.84,0.65)

0.46(-0.24,1.17) 0.3(-0.36,0.97) 0.15(-0.62,0.92)

−0.1(-0.83,0.62) 0.03(-0.66,0.72) 0.39(-0.34,1.11)

0.00(-0.47,0.48) 0.19(-0.27,0.65) −0.06(-0.51,0.39)

0.77(0.15,1.38) 0.11(-0.47,0.69) 0.06(-0.55,0.66)

0.64(0.18,1.09) −0.12(-0.52,0.29) 0.06(-0.39,0.51)

0.35(-0.07,0.76) 0.24(-0.14,0.62) −0.33(-0.72,0.07)

0.01(-0.51,0.53) 0.16(-0.37,0.69) 0.41(-0.13,0.96)

adjusted β (95% CI)

DBP b

0.08 0.51 0.08

0.84 0.80 0.99

0.96 0.96 0.96

0.63 0.84 0.96

0.96 0.99 0.79

0.99 0.84 0.96

0.08 0.96 0.98

0.08 0.96 0.96

0.51 0.63 0.51

0.99 0.96 0.53

P-FDR

d

0.60(0.08,1.12) 0.87(0.06,1.68) 1.08(-0.01,2.18)

0.89(-0.51,2.30) 0.79(-0.35,1.93) −0.32(-1.64,1.01)

0.14(-1.11,1.39) 0.23(-0.85,1.31) −0.13(-1.32,1.06)

1.23(-0.02,2.48) 0.79(-0.33,1.91) 0.06(-1.19,1.32)

−0.33(-1.56,0.90) −0.06(-1.21,1.09) −0.24(-1.45,0.97)

0.37(-0.47,1.21) 0.35(-0.42,1.12) −0.62(-1.42,0.18)

0.71(-0.28,1.70) −0.20(-1.22,0.82) 0.13(-0.94,1.19)

0.60(-0.16,1.35) −0.38(-1.11,0.36) 0.14(-0.67,0.95)

0.32(-0.35,1.00) 0.22(-0.42,0.86) −0.09(-0.80,0.63)

−0.34(-1.23,0.54) 0.44(-0.52,1.39) 0.47(-0.46,1.40)

adjusted β (95% CI)

SBP c

0.38 0.38 0.38

0.63 0.60 0.89

0.89 0.89 0.89

0.38 0.60 0.92

0.89 0.92 0.89

0.73 0.73 0.60

0.60 0.89 0.89

0.60 0.73 0.89

0.73 0.83 0.89

0.79 0.73 0.73

P-FDR

d

Women with male fetus (n = 330)

0.57(0.11,1.03) 0.98(0.16,1.79) 1.10(-0.2,2.41)

0.60(-0.54,1.75) 0.51(-0.41,1.44) −0.01(-1.09,1.07)

0.07(-0.95,1.09) 0.23(-0.65,1.11) −0.17(-1.14,0.80)

0.60(-0.42,1.61) 0.55(-0.35,1.46) 0.12(-0.91,1.14)

−0.18(-1.18,0.82) 0.13(-0.81,1.06) 0.10(-0.88,1.08)

0.06(-0.62,0.75) 0.16(-0.47,0.78) −0.16(-0.82,0.49)

0.88(0.08,1.69) 0.04(-0.79,0.87) 0.00(-0.87,0.86)

0.68(0.08,1.29) −0.31(-0.91,0.28) −0.10(-0.75,0.56)

0.55(0.01,1.10) 0.30(-0.23,0.82) −0.27(-0.85,0.31)

−0.16(-0.88,0.55) 0.50(-0.28,1.27) 0.43(-0.32,1.18)

adjusted β (95% CI)

DBP

Abbreviations: CI, confidence interval. ΣDEHP: the molar sum of MEHP (292 g/mol), MEOHP (292 g/mol), MEHHP (294 g/mol), and MECPP (308 g/mol). ΣLMW: the molar sum of MEP (194 g/mol), MiBP (222 g/mol), and MnBP (222 g/mol). a The unit is nmol/L. b Adjusted for gestational age, household income, pre-pregnancy BMI, gestational diabetes mellitus, parity, fetus gender. c Adjusted for gestational age, household income, pre-pregnancy BMI, gestational diabetes mellitus, parity. d P values for estimating false-discovery rate (FDR) to correct multiple comparisons.

MEP 1st trimester 2nd trimester 3rd trimester MiBP 1st trimester 2nd trimester 3rd trimester MnBP 1st trimester 2nd trimester 3rd trimester ΣLMWa 1st trimester 2nd trimester 3rd trimester MEHP 1st trimester 2nd trimester 3rd trimester MECPP 1st trimester 2nd trimester 3rd trimester MEHHP 1st trimester 2nd trimester 3rd trimester MEOHP 1st trimester 2nd trimester 3rd trimester ΣDEHPa 1st trimester 2nd trimester 3rd trimester ERS 1st trimester 2nd trimester 3rd trimester

Chemicals (ng/L)

Table 5 Associations between ln-transformed urinary phthalate metabolite concentrations (SG-adjusted) and blood pressure in the 3rd trimester.

c

0.23 0.23 0.50

0.66 0.66 0.99

0.99 0.99 0.99

0.66 0.66 0.99

0.99 0.99 0.99

0.99 0.99 0.99

0.23 0.99 0.99

0.23 0.66 0.99

0.24 0.66 0.72

0.99 0.66 0.66

P-FDR

d

0.54 0.53 0.15

1.00 1.00 1.00

−0.37(-1.66,0.92) −0.19(-1.49,1.11) −0.08(-1.64,1.47) 1.16(-0.19,2.51) 0.71(-0.05,1.48) 0.88(0.21,1.54)

1.00 1.00 1.00

1.00 1.00 1.00

−0.15(-1.39,1.08) −0.24(-1.47,0.99) −0.07(-1.56,1.41) −0.27(-1.49,0.95) −0.21(-1.46,1.03) −0.19(-1.68,1.31)

1.00 0.96 1.00

1.00 1.00 1.00

−0.12(-0.96,0.71) 0.05(-0.81,0.91) −0.04(-0.80,0.72) −0.44(-1.77,0.88) −0.65(-1.94,0.64) 0.23(-1.12,1.58)

1.00 0.60 0.60

0.00(-1.19,1.19) 0.75(-0.26,1.76) 0.78(-0.28,1.84)

1.00 1.00 0.73

1.00 0.53 1.00

−0.25(-1.07,0.58) 0.63(-0.06,1.32) 0.00(-0.66,0.67) 0.04(-0.82,0.90) 0.29(-0.39,0.98) 0.47(-0.28,1.22)

0.60 1.00 0.15

c

P-FDR

0.68(-0.28,1.64) 0.34(-0.57,1.25) 1.22(0.24,2.20)

adjusted β (95% CI)

SBP

d

Women with female fetus (n = 303)

0.76(-0.18,1.71) 1.18(-0.75,3.11) 0.21(-0.96,1.38)

0.14(-0.90,1.17) 0.09(-0.95,1.13) 0.14(-1.10,1.39)

0.28(-0.70,1.25) −0.07(-1.06,0.92) −0.01(-1.21,1.19)

0.39(-0.60,1.38) −0.06(-1.04,0.93) 0.14(-1.05,1.32)

0.06(-1.00,1.12) −0.14(-1.17,0.90) 0.80(-0.28,1.88)

0.01(-0.66,0.68) 0.27(-0.41,0.96) 0.06(-0.54,0.67)

0.51(-0.45,1.46) 0.17(-0.64,0.98) 0.12(-0.73,0.96)

0.52(-0.17,1.20) 0.05(-0.49,0.60) 0.20(-0.40,0.81)

−0.10(-0.76,0.56) 0.15(-0.41,0.70) −0.39(-0.92,0.15)

0.26(-0.51,1.03) −0.20(-0.93,0.53) 0.37(-0.42,1.16)

adjusted β (95% CI)

DBP c

0.98 0.98 0.98

0.98 0.98 0.98

0.98 0.98 0.99

0.98 0.98 0.98

0.98 0.98 0.98

0.99 0.98 0.98

0.98 0.98 0.98

0.98 0.98 0.98

0.98 0.98 0.98

0.98 0.98 0.98

P-FDR

d

X. Han, et al.

Ecotoxicology and Environmental Safety xxx (xxxx) xxxx

0.12(-0.62,0.86) 0.33(-0.21,0.87) 0.31(-0.29,0.90) 0.73(-0.13,1.59) −0.33(-1.01,0.35) −0.27(-1.31,0.78) 0.03(-1.01,1.07) −0.12(-1.14,0.89) −0.07(-1.19,1.05) 0.77(-0.15,1.70)

adjusted β (95% CI)

SBP

b

0.95 0.95 0.95 0.68 0.95 0.68 0.68 0.95 0.50 0.50

P-FDR

All participants (n = 633) d

0.28(-0.37,0.93) 0.08(-0.40,0.55) −0.11(-0.63,0.40) 0.22(-0.53,0.97) 0.07(-0.52,0.67) 0.04(-0.87,0.96) 0.24(-0.67,1.15) 0.21(-0.68,1.10) 0.29(-0.69,1.27) 0.99(-0.70,2.69)

adjusted β (95% CI)

DBP b

0.90 0.90 0.93 0.90 0.90 0.90 0.90 0.90 0.90 0.90

P-FDR

d

0.31(-0.71,1.32) 0.69(-0.02,1.40) 0.35(-0.48,1.18) 1.30(0.13,2.47) −0.77(-1.69,0.15) −0.93(-2.27,0.40) −0.82(-2.21,0.57) −0.96(-2.30,0.39) −0.81(-2.32,0.70) 0.82(0.22,1.41)

adjusted β (95% CI)

SBP c

0.36 0.46 0.56 0.20 0.28 0.25 0.28 0.36 0.10 0.15

P-FDR

d

Women with male fetus (n = 330)

0.69(-0.15,1.54) 0.51(-0.09,1.10) 0.11(-0.58,0.80) 0.88(-0.09,1.85) −0.30(-1.06,0.47) −0.24(-1.36,0.87) −0.16(-1.31,1.00) −0.10(-1.22,1.02) 0.01(-1.25,1.27) 0.80(0.10,1.51)

adjusted β (95% CI)

DBP c

0.96 0.96 0.99 0.28 0.96 0.28 0.90 0.96 0.28 0.28

P-FDR

d

8

6.39(-1.53,14.32) 2.96(-2.48,8.41) 4.34(-3.2,11.89) 9.92(-2.62,22.46) −0.06(-0.82,0.70) −5.30(-16.80,6.19) 6.76(-5.05,18.58) 1.00(-11.95,9.95) 0.38(-1.00,1.76) 0.62(0.01,1.24)

adjusted β (95% CI)

SBP

b

0.74 0.87 0.87 0.40 0.48 0.48 0.48 0.53 0.40 0.40

P-FDR

All participants (n = 633) d

2.60(-3.78,8.98) 1.31(-3.07,5.69) 3.48(-2.59,9.54) 7.62(-2.46,17.71) 0.06(-0.55,0.67) 1.25(-8.00,10.49) 6.03(-3.47,15.52) 0.61(-8.19,9.41) 0.56(-0.55,1.66) 0.57(-0.18,1.33)

adjusted β (95% CI)

DBP b

0.89 0.89 0.89 0.65 0.70 0.65 0.66 0.80 0.65 0.65

P-FDR

d

c

2.28(-8.55,13.11) 2.45(-5.22,10.12) 2.33(-8.40,13.05) 6.11(-11.69,23.91) 0.02(-1.06,1.11) −5.23(-20.48,10.03) 13.94(-2.35,30.23) 0.42(-14.24,15.07) 1.03(-0.85,2.91) 0.73(-0.16,1.62)

adjusted β (95% CI)

SBP

0.85 0.85 0.85 0.85 0.97 0.85 0.55 0.97 0.85 0.55

P-FDR

d

Women with male fetus (n = 330)

c

2.85(-5.94,11.65) 3.49(-2.73,9.72) 1.91(-6.81,10.62) 8.54(-5.91,22.98) 0.00(-0.88,0.89) −0.58(-12.98,11.82) 8.77(-4.49,22.03) 0.30(-11.61,12.21) 0.79(-0.74,2.32) 0.68(-0.19,1.54)

adjusted β (95% CI)

DBP

Abbreviations: CI, confidence interval. ΣDEHP: the molar sum of MEHP (292 g/mol), MEOHP (292 g/mol), MEHHP (294 g/mol), and MECPP (308 g/mol). ΣLMW: the molar sum of MEP (194 g/mol), MiBP (222 g/mol), and MnBP (222 g/mol). a The unit is nmol/L. b Adjusted for gestational age, household income, pre-pregnancy BMI, gestational diabetes mellitus, parity, fetus gender. c Adjusted for gestational age, household income, pre-pregnancy BMI, gestational diabetes mellitus, parity. d P values for estimating false-discovery rate (FDR) to correct multiple comparisons.

MEP MiBP MnBP ΣLMWa MEHP MECPP MEHHP MEOHP ΣDEHPa ERS

Chemicals (ng/L)

1.00 1.00 1.00 0.62 0.87 0.62 0.62 0.96 0.62 0.62

P-FDR

d

Table 7 Associations between ln-transformed average concentrations of phthalates (SG-adjusted) during pregnancy and blood pressure in the 3rd trimester.

Abbreviations: CI, confidence interval. ΣDEHP: the molar sum of MEHP (292 g/mol), MEOHP (292 g/mol), MEHHP (294 g/mol), and MECPP (308 g/mol). ΣLMW: the molar sum of MEP (194 g/mol), MiBP (222 g/mol), and MnBP (222 g/mol). a The unit is nmol/L. b Adjusted for gestational age, household income, pre-pregnancy BMI, gestational diabetes mellitus, parity, fetus gender. c Adjusted for gestational age, household income, pre-pregnancy BMI, gestational diabetes mellitus, parity. d P values for estimating false-discovery rate (FDR) to correct multiple comparisons.

MEP MiBP MnBP ΣLMWa MEHP MECPP MEHHP MEOHP ΣDEHPa ERS

Chemicals (ng/L)

c

0.74 0.94 1.00 0.64 0.74 0.64 0.64 0.74 0.64 0.64

P-FDR

d

c

11.36(-0.34,23.06) 2.15(-5.61,9.92) 5.68(-4.96,16.33) 12.57(-5.12,30.25) −0.06(-1.12,0.99) −5.78(-23.46,11.89) −3.49(-20.68,13.71) −4.44(-21.07,12.18) −0.48(-2.51,1.56) 0.82(0.04,1.59)

adjusted β (95% CI)

SBP

0.77 0.77 0.91 0.53 0.77 0.75 0.77 0.77 0.30 0.30

P-FDR

d

Women with female fetus (n = 303)

−0.10(-1.20,1.00) −0.25(-1.09,0.58) 0.24(-0.62,1.10) 0.00(-1.27,1.28) 0.31(-0.71,1.33) 0.86(-0.82,2.55) 1.22(-0.35,2.78) 1.06(-0.50,2.61) 0.96(-0.71,2.63) 0.44(-0.36,1.23)

adjusted β (95% CI)

SBP

Women with female fetus (n = 303)

Table 6 Associations between ln-transformed average concentrations of phthalates (SG-adjusted) in the 1st and the 2nd trimester and blood pressure in the 2nd trimester.

2.12(-7.30,11.54) −1.76(-7.98,4.46) 4.73(-3.80,13.25) 5.89(-8.30,20.08) 0.18(-0.67,1.03) 4.23(-9.93,18.38) 2.63(-11.14,16.40) 0.98(-12.34,14.30) 0.29(-1.34,1.91) 1.01(-0.38,2.41)

adjusted β (95% CI)

DBP

−0.17(-1.18,0.84) −0.51(-1.28,0.25) −0.32(-1.11,0.48) −0.51(-1.68,0.66) 0.61(-0.32,1.55) 0.54(-1.01,2.10) 0.77(-0.68,2.21) 0.65(-0.78,2.08) 0.68(-0.86,2.22) 1.04(0.16,1.91)

adjusted β (95% CI)

DBP

c

c

0.81 0.81 0.89 0.81 0.81 0.81 0.81 0.81 0.81 0.81

P-FDR

0.54 0.54 0.74 0.54 0.54 0.54 0.54 0.54 0.20 0.54

P-FDR

d

d

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Conceptualization, Methodology Yuanyuan Li: Conceptualization, Project administration, Hongxiu Liu: Investigation, Data Curation, Yanqiu Zhou: Investigation, Data Curation, Hongzhi Zhao: Investigation, Data Curation, Jing Fang: Investigation, Data Curation Zongwei Cai: Conceptualization, Methodology, Resources, Writing Review &, Editing, Wei Xia: Conceptualization, Methodology, Resources, Writing - Review & Editing.

The possible mechanisms of elevated blood pressure associated with phthalates in pregnant women remains unknown, but the existing research results may provide some evidences. Exposure to phthalates was related to increased oxidative stress in pregnant women (Ferguson et al., 2015), and oxidative stress may influence the release of the circulating angiogenic factors which are predictors for preeclampsia (Burton et al., 2009; Levine RJ et al., 2004). Furthermore, phthalates may affect blood pressure by altering the level of thyroid hormone during pregnancy. A previous study found that urinary phthalates were associated with decreased serum thyroxin in pregnant women (Yao et al., 2016), which is proved to increase the risk of preeclampsia (Zhang et al., 2017). Meanwhile, phthalate-induced inflammatory responses could be a significant mechanism of gestational hypertension. A research conducted among pregnant women found that some urinary phthalate metabolites were associated with higher concentration of inflammation cytokines (van et al., 2019). The increased production of inflammatory cytokines may be an important factor in gestational hypertension or preeclampsia (Harmon et al., 2016). Our results suggested that associations between phthalates exposure and blood pressure varied among the groups stratified by fetus gender. MiBP and ΣLMW exposed in the first trimester were positively associated with DBP in the second trimester among women with male fetuses, and the adverse direction was observed among women with female fetuses with non-significant estimation. Phthalates may affect blood pressure by altering the level of thyroid hormone during pregnancy in a fetal sex-specific way (Chen et al., 2007; Gore et al., 2015). In addition, phthalates-induced inflammatory responses may differ between fetal sex, which may also contribute to the difference (Enninga et al., 2015). Based on the advantages of prospective cohort design, we collected spot urine samples and measured blood pressures in three trimesters respectively, which could examine the trimester-specific association throughout pregnancy. Besides, we adjusted for potential confounders. A face-to-face interview was conducted with each participant and detailed information about socioeconomic and demographic characteristics were collected. However, our study had some limitations. First, the concentration of single spot urine may not adequately represent the exposure level of the entire trimester, for phthalates can rapidly metabolized and eliminated from the body (within hours of exposure). Next, most of the participants took blood pressure measurements on the same day of urine collection. We were unable to carry out a further analysis by restricting in these women whose blood pressures were taken following the day of urine collection to protect against reverse causation. Furthermore, although we adjusted for most confounders, we cannot eliminate the residual caused by other unmeasured factors that may affect blood pressure. The life style, dietary habit, environment temperature and many other factors may induce hypertension. Besides, the mechanism how phthalates affect blood pressure during pregnancy was not yet well investigated, which should be taken into consideration in future researches.

Declaration of competing interest None. Acknowledgements This work was supported by the National Key Research and Development Plan of China [grant numbers: 2016YFC0206700, 2016YFC0206203], the National Natural Science Foundation of China [grant numbers: 81372959, 21437002, 81402649, 91643207 and 21777010]. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ecoenv.2019.109944. References Al-Qaraghouli, M., Fang, Y.M.V., 2017. Effect of fetal sex on maternal and obstetric outcomes. Front Pediatr 5, 144. Bakker, R., Steegers, E.A., Hofman, A., Jaddoe, V.W., 2011. Blood pressure in different gestational trimesters, fetal growth, and the risk of adverse birth outcomes: the generation R study. Am. J. Epidemiol. 174, 797–806. Bekö, G., Weschler, C.J., Langer, S., Callesen, M., Toftum, J., Clausen, G., 2013. Children's phthalate intakes and resultant cumulative exposures estimated from urine compared with estimates from dust ingestion, inhalation and dermal absorption in their homes and daycare centers. PLoS One 8, e62442. Benjamin, S., Masai, E., Kamimura, N., Takahashi, K., Anderson, R.C., Faisal, P.A., 2017. Phthalates impact human health: epidemiological evidences and plausible mechanism of action. J. Hazard Mater. 340, 360–383. Bernhardt, P.W., Wang, H.J., Zhang, D., 2015. Statistical methods for generalized linear models with covariates subject to detection limits. Stat Biosci 7, 68–89. Brown, R.N., 2016. Maternal adaptation to pregnancy is at least in part influenced by fetal gender. BJOG 123, 1096. Burton, G.J., Yung, H.W., Cindrova-Davies, T., Charnock-Jones, D.S., 2009. Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta 30 (Suppl. A), S43–S48. Chen, J., Ahn, K.C., Gee, N.A., Gee, S.J., Hammock, B.D., Lasley, B.L., 2007. Antiandrogenic properties of parabens and other phenolic containing small molecules in personal care products. Toxicol. Appl. Pharmacol. 221, 278–284. Chinese society of obstetrics and gynecology pregnancy hypertension group, 2015. Guidelines for diagnosis and treatment of hypertensive disorders of pregnancy. Chin. J. Obstet. Gynecol. 50 (10), 721–728 (In Chinese). De Toni, L., Tisato, F., Seraglia, R., Roverso, M., Gandin, V., Marzano, C., Padrini, R., Foresta, C., 2017. Phthalates and heavy metals as endocrine disruptors in food: a study on pre-packed coffee products. Toxicol Rep 4, 234–239. Dinse, G.E., Jusko, T.A., Ho, L.A., Annam, K., Graubard, B.I., Hertz-Picciotto, I., et al., 2014. Accommodating measurements below a limit of detection: a novel application of cox regression. Am. J. Epidemiol. 179, 1018–1024. Du, Y.Y., Fang, Y.L., Wang, Y.X., Zeng, Q., Guo, N., Zhao, H., Li, Y.F., 2016. Follicular fluid and urinary concentrations of phthalate metabolites among infertile women and associations with in vitro fertilization parameters. Reprod. Toxicol. 61, 142–150. Dunietz, G.L., Strutz, K.L., Holzman, C., Tian, Y., Todem, D., Bullen, B.L., Catov, J.M., 2017. Moderately elevated blood pressure during pregnancy and odds of hypertension later in life: the POUCHmoms longitudinal study. BJOG 124, 1606–1613. Enninga, E.A., Nevala, W.K., Creedon, D.J., Markovic, S.N., Holtan, S.G., 2015. Fetal sexbased differences in maternal hormones, angiogenic factors, and immune mediators during pregnancy and the postpartum period. Am. J. Reprod. Immunol. 73, 251–262. Ferguson, K.K., McElrath, T.F., Cantonwine, D.E., Mukherjee, B., Meeker, J.D., 2015. Phthalate metabolites and bisphenol-A in association with circulating angiogenic biomarkers across pregnancy. Placenta 36, 699–703. Giovanoulis, G., Bui, T., Xu, F., Papadopoulou, E., Padilla-Sanchez, J.A., Covaci, A., Haug, L.S., Cousins, A.P., Magner, J., Cousins, I.T., de Wit, C.A., 2018. Multi-pathway human exposure assessment of phthalate esters and DINCH. Environ. Int. 112, 115–126. Gore, A.C., Chappell, V.A., Fenton, S.E., Flaws, J.A., Nadal, A., Prins, G.S., et al., 2015. Edc-2: the endocrine society's second scientific statement on endocrine-disrupting

5. Conclusions The present study revealed that exposure to phthalates was positively related to blood pressure in pregnant women, though the increment is marginal. These findings still have important implications, since increased blood pressure, even not met the threshold of hypertension, may induce potentially significant health consequences in pregnant women. Author Contributions Section Xiaoyu Han; Validation, Formal analysis, Writing - Original Draft, Jiufeng Li; Validation, Formal analysis, Writing - Original Draft, Youjie Wang; Conceptualization, Writing - Review & Editing, Shunqing Xu: 9

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