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Association of adverse birth outcomes with prenatal uranium exposure: A population-based cohort study
Environment International 135 (2020) 105391
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Association of adverse birth outcomes with prenatal uranium exposure: A population-based cohort study
T
Weiping Zhanga,1, Wenyu Liua,1, Shuangshuang Baoa, Hongxiu Liua, Yuzeng Zhanga, Bin Zhangb, ⁎ ⁎ Aifen Zhoub, Jia Chenc, Ke Haod, Wei Xiaa, Yuanyuan Lia, Xia Shenga, , Shunqing Xua, a Key Laboratory of Environment and Health (HUST), Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China b Wuhan Women and Children Medical Care Center, Wuhan, Hubei, China c Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA d Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
A R T I C LE I N FO
A B S T R A C T
Handling Editor: Mark Nieuwenhuijsen
Uranium (U) is a well-recognized hazardous heavy metal with embryotoxicity and fetotoxicity. However, little is known about its association with adverse birth outcomes. We aimed to investigate the potential correlation between prenatal U exposure and birth outcomes. Urine samples of 8500 women were collected before delivery from a birth cohort in Wuhan, China. Concentrations of urinary U and other metals were measured by inductively coupled plasma mass spectrometry. We used multivariable logistic regressions to evaluate the associations between urinary U concentrations and adverse birth outcomes, such as preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA). Associations of urinary U concentrations with gestational age, birth weight, and birth length were investigated by linear regressions. The geometric mean of U concentration was 0.03 μg/L. After adjustment for potential confounders, we found each Log2-unit increase in U concentration was associated with a significant decrease in gestational age [adjusted β = −0.32 day; 95% confidence interval (CI): −0.44, −0.20] and a significant increased likelihood of PTB (adjusted OR = 1.18, 95% CI: 1.07, 1.29). This birth cohort uncovered an association of maternal exposure to U during pregnancy with decreased gestational age and increased risk of PTB. Our findings reveal an association of maternal exposure to U during pregnancy with decreased gestational age and increased risk of PTB.
Keywords: Adverse birth outcomes Gestational age Prenatal exposure Preterm birth Uranium
1. Introduction Uranium (U) is a heavy metal with both chemical toxicity and radioactivity. In the environment, U can be detected in rocks, soil and groundwater, with the 238U being the most common isotope of the element (> 99.27%) (Domingo, 2001). In recent decades, U has been widely used in nuclear power reactors and nuclear weapons, which has also led to environmental pollution and serious health safety concerns. Similar to many other heavy metals, there are mainly two types of U exposure, acute high-level exposure due to occupational reasons, and chronic low-dose exposure for the general population either by inhalation or by dietary intake (Keith et al., 2013; May et al., 2004). U can enter the human body via air, food or drinking water, where it is taken up in the blood (Keith et al., 2013; Selden et al., 2009). Approximately 67% of U in the blood is filtered in the kidneys and leaves
the body in urine, with a half-life between 12 and 24 h, providing a rationale for measuring U exposure by urinalysis (May et al., 2004). U exposure can cause significant renal damage, but the toxic effect is not restricted to the kidney. A number of recent animal studies have shown that adulthood U exposure affect the function of various organs, including the intestine, reproductive system, and brain (Dublineau et al., 2007; Feugier et al., 2008; Legendre et al., 2016; Lestaevel et al., 2005). In particular, high dose of maternal U exposure during pregnancy could cause developmental toxicity in fetuses in mice (Domingo et al., 1989; Paternain et al., 1989). However, detailed molecular mechanism underlying these phenomena is not fully understood. Adverse birth outcomes, such as preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA) represent significant health problems across the globe. PTB, defined as birth occurring before 37 completed weeks of gestation, is the leading contributor to neonatal
⁎
Corresponding authors. E-mail addresses: [email protected] (X. Sheng), [email protected] (S. Xu). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.envint.2019.105391 Received 29 August 2019; Received in revised form 10 October 2019; Accepted 3 December 2019 0160-4120/ © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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Urine (SRM2670a Toxic Elements in Urine; National Institute of Standards and Technology, Gaithersburg, MD, USA) was used as an external quality-control sample in each batch to improve the accuracy of the measurements, and the concentrations measured were within the certified range. LOD was determined according to the previously described equation LOD = 3RSDb × C/SBR (Boumans et al., 1991). The limit of detection (LOD) for U was 1.5 × 10−4 μg/L. The recovery of the quality control standard by using this procedure was 99.75%. The intra-day coefficient of variation (CV) was 0.86%, and inter-day CV was 2.59%. Urine creatinine concentrations were measured by a creatinine kit (Mindray BS-200 CREA Kit, Shenzhen Mindray Bio-medical Electronics Co., Ltd).
death (Frey and Klebanoff, 2016). Its potential adverse impact may extend to later life periods on medical, psychological, behavioral and social aspects (Moster et al., 2008). LBW infants, weighing less than 2500 g at (2002), display a 25-fold increase in mortality rate relative to their normal counterparts (Mathews and MacDorman, 2008). SGA babies normally refer to those whose birth weights are below the 10th percentile for the gestational age. They are possibly at increased risk of cardiovascular disease and diabetes in adulthood (McCowan et al., 2010; McCowan et al., 2017). Recent epidemiological studies from us and others have suggested that maternal environmental exposures to heavy metals, such as lead (Pb), arsenic (As), cadmium (Cd) and thallium (Tl), are associated with increased risks of various adverse birth outcomes, including PTB, SGA and LBW (Jiang et al., 2018; Odland et al., 1999; Rahman et al., 2009; Yang et al., 2016). Despite the known toxicity of U, Bloom et al. failed to observe an association of maternal urinary U concentration with birth size and gestational age, instead they found that higher paternal urinary U level was correlated with lower birth weight and shorter birth length (Bloom et al., 2015). Therefore, whether maternal U exposure during pregnancy has an effect on birth outcomes remains to be characterized. To this end, taking advantage of a large birth cohort in Wuhan, China, the present study aimed to investigate the correlations between prenatal U exposure and the risk of adverse birth outcomes, including PTB, LBW, SGA and other birth outcomes, such as gestational age, birth weight and birth length.
2.3. Data collection Face to face interviews were conducted by well-trained interviewers within three days before or after delivery to collect maternal sociodemographic characteristics and life style factors, including maternal age, occupational status, education background, tobacco use, passive smoking and alcohol consumption. Information on pregnancy complications, parity, fetal sex, birth weight and birth length were obtained from medical records. Gestational age was calculated based on ultrasound measurements in the first trimester. The pre-pregnancy BMI was calculated using pre-pregnancy body weight and height. Pre-pregnancy body weight was self-reported and height was measured using a stadiometer in hospital. Additionally, pre-pregnancy BMI was categorized into four classes based on the Chinese standard (underweight: < 18.5 kg/m2, normal: 18.5–23.9 kg/m2, overweight: 23.9–27.9 kg/m2, and obese: ≥28.0 kg/m2) (Zhou et al., 2002).
2. Methods 2.1. Study population The present study was a part of a prospective birth cohort study that recruited pregnant women in Wuhan Women and Children’s Medical Care Center from 2012 to 2014 in Wuhan, China. Pregnant women who met the following criteria were recruited: (a) with a singleton gestation and live birth; (b) resident of Wuhan City; (c) ability to comprehend the Chinese language without communication problem. All participants provided written informed consent at enrollment. Ethical approval for the study was approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology, and Wuhan Women and Children’s Medical Care Center. During September 2012 and October 2014, we enrolled 8565 pregnant women with spot urine samples. Women who gave birth to an infant with a birth defect were excluded (n = 65), leaving the final analysis with 8,500 mother-infant pairs.
2.4. Study outcomes The study outcomes include adverse birth outcomes (PTB, LBW and SGA), gestational age, birth weight and birth length. PTB was defined as babies born alive before 37 weeks of pregnancy are completed. LBW was referred to a birth weight less than 2500 g. SGA was defined as a birth weight below the 10th percentile for the gestational age by infant sex based on all the newborns in our birth cohort from Wuhan. 2.5. Statistical analysis For analysis, values for U concentrations below the LOD was replaced by one-half LOD (Harel et al., 2014). As the Shapiro-Wilk normality test showed that the urinary metal concentrations were highly skewed, the geometric mean and percentiles of urinary metal concentrations were calculated, and Log2 transformations of the values were applied for urinary metal concentrations before analyses. We next examined the association between urinary U levels and sociodemographic characteristics using general linear models. Beta coefficients from the general linear models were exponentiated to produce the ratio of urinary U levels between different categories of demo-socioeconomic characteristics. The values above or below 1.0 means that urinary U concentrations were respectively higher or lower in that category compared to the reference category. In addition, we calculated Pearson correlation coefficients using Log2-transformed concentrations of metals. We used linear regression models to estimate the association of Log2-transformed urinary U concentrations (Log2-U, as a continuous variable) with continuous birth outcomes (gestational age, birth weight and birth length). Logistic regression models were also performed to assess the association of Log2-transformed urinary U concentrations (Log2-U, as a continuous variable) with the risk of birth outcomes (PTB, LBW and SGA). To test potential non-linear dose-response relationship, we also assessed the association between U concentration quartiles (as a categorical variable, and the lowest quartile was assigned as the reference)
2.2. Urine sample collection and U measurements Spot urine samples were collected from pregnant women immediately after they were admitted to the hospital for delivery (within 3 days prior to delivery). Urine samples were stored in the 5 mL polypropylene tubes at −20 °C until further analysis. Inductively coupled plasma mass spectrometry (ICP-MS) (Agilent 7700, Agilent Technologies) was used to analyze the urinary U concentrations. Urine samples were first thawed at room temperature (20–25 °C). After being thoroughly vortexed, they were added into 15 mL polypropylene tubes with 1.2% (v/v) nitric acid (HNO3) for overnight nitrification. Next, the resulting samples were digested by ultrasound at 40 °C for one hour, and U was measured by ICP-MS. Urinary total arsenic (As), lead (Pb), thallium (Tl) and cadmium (Cd) levels were also measured by the same method. The operating parameters for ICP-MS were as follows: radio frequency power 1550 W, plasma gas flow 15.00 L/min, auxiliary gas flow 0.8 L/min, carrier gas flow 0.8 L/min, resolution (peak high 10%) 0.65–0.80 amu, sample uptake rate 0.4 mL/min, unimodal residence time 0.30 s (0.99 s for Cd), repetitions 3 times. Stringent laboratory quality controls were implemented to ensure the accuracy of the analyses. The Standard Reference Material Human 2
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concentrations remained inversely associated with gestational age and the associations became slightly stronger. Moreover, birth weight (adjusted β = 0.60 g, 95% CI: −5.37, 6.56) and birth length (adjusted β = −0.01 cm; 95% CI: −0.03, 0.01) were not associated with urinary U concentrations. But after additional adjustment for other metals, significant association of U with birth weight [adjusted β = −6.65 g, 95% CI: −13.09, −0.20; quartile 1 = 1; quartile 2 = −28.53 (95% CI: −54.01, −3.05); quartile 3 = −27.13 (95% CI: −52.96, −1.29); quartile 4 = −22.82 (95% CI: −49.55, 3.91); P for trend = 0.1301] and birth length [adjusted β = −0.03 cm, 95% CI:−0.06, −0.01; quartile 1 = 1; quartile 2 = −0.10 (95% CI: −0.20, 0.00); quartile 3 = −0.09 (95% CI: −0.18, 0.01); quartile 4 = −0.12 (95% CI: −0.22, −0.02); P for trend = 0.0508] was found. The odds ratios (ORs) and 95% CIs for adverse birth outcomes including PTB, LBW and SGA according to maternal urinary U concentrations (μg/L) are shown in Table 4. The adjusted OR for per unit increase in Log2-U concentrations was 1.14 (95% CI: 1.05, 1.24) for PTB. Women who were in the highest quartile of U concentration (urinary U concentrations > 0.06 μg/L) displayed about 1.59 fold increased risk of preterm delivery (adjusted OR: 1.59, 95% CI: 1.15, 2.21, P for trend: 0.0052) compared with women who were in the lowest quartile (urinary U concentrations < 0.02 μg/L). After additional adjustment for other metals, the ORs of PTB for increase in Log2-U concentrations became slightly higher. In addition, maternal urinary U concentrations was not significantly correlated with the likelihood of LBW (adjusted OR: 0.97, 95% CI: 0.89, 1.07) and SGA (adjusted OR: 0.97, 95% CI: 0.92, 1.02). Lastly, in the sensitivity analyses excluding mothers with creatinine concentrations below 0.3 g/L or above 3 g/L (6286 mother-infant pairs included), the association of urinary U concentration with birth outcomes were similar to the results of primary analyses (Tables S2 and S3).
and birth outcomes using regression models described above. Tests for linear trend were conducted by modeling the median value of each quartile to test ordered relations across quartiles of urinary U concentrations. All multivariate regression models were adjusted for maternal age (< 25 y, 25–29 y, 30–34 y, ≥35 y), maternal education (compulsory or lower, high school or equivalent, graduate or higher), parity (nulliparous, multiparous), pre-pregnancy BMI (< 18.5 kg/m2, 18.5–23.9 kg/m2, 23.9–27.9 kg/m2, ≥28.0 kg/m2), passive smoking, hypertensive disorders in pregnancy, gestational diabetes mellitus, fetal sex and paternal height (in birth length models). We chose these potential confounders for being previously reported to associate with birth outcomes or U exposures, or if they resulted in a > 10% change in the main effect estimates. Furthermore, as previous studies from ours (using the same cohort) as well as others have associated As, Pb, Tl and Cd with adverse birth outcomes (Ahmad et al., 2001; Cheng et al., 2017; Jiang et al., 2018; Yang et al., 2016), we also adjusted all regression models for urinary total As, Pb, Tl and Cd. Except for paternal height, and urinary concentrations of total As, Pb, Tl and Cd, all the potential confounders were categorical variables. Owing to the low rates of maternal smoking (9/ 8500, 0.11%) and alcohol use (2/8500, 0.02%) during pregnancy in this cohort, these factors were not adjusted for. Missing values of categorical variable were grouped into another category to avoid losing samples due to missing values of confounders. Due to the functional impact of pregnancy on kidney physiology, pregnant women often exhibit gestational glomerular hyperfiltration, which leads to an expected decrease in urinary creatinine (Cheung and Lafayette, 2013). Thus, we entered creatinine as a covariate instead of using creatinine-corrected U concentrations to accommodate urine dilution. To further rule out the possible impact in this regard, we also conducted a sensitivity analysis only including women with urinary creatinine concentrations between 0.3 g/L and 3.0 g/L (n = 6286). Statistical analyses were performed using SAS (version9.4; SAS Institute Inc.). Two-sided p < 0.05 was considered statistically significant.
4. Discussion This prenatal cohort study investigated the associations of U exposure with birth outcomes in a large population of 8500 women recruited in Wuhan, China. Based on the measurement of urinary U concentrations shortly prior to delivery, we observed significant associations of increased prenatal urinary U concentration with shortened gestational age and higher risk of PTB. For most people, ingestion is the most common pathway of exposure to U, and the absorbed U is excreted in urine mostly as uranyl ions, thus the exposure level can be determined by measuring the urinary U concentration (Keith et al., 2013; Selden et al., 2009). In this study, U was detected in 99.13% of the maternal urine samples, indicating that our study population was widely exposed to U, at least during pregnancy. Comparatively, the urinary U concentrations in our study (GM, 0.03 μg/L; median, 0.03 μg/L) was higher than those of pregnant women in Australia (GM, 0.013 μg/L; median, 0.005 μg/L) and USA (GM, 0.006 μg/L) (Callan et al., 2013; Jain, 2013), but lower than those of the general population in Saharawi (median, 0.15 μg/L) and South Carolina (median, 0.162 μg/L) (Aakre et al., 2018; Orloff et al., 2004). Wuhan is a major heavy industry city in Central China with many coalfired power plants and steelworks, and coal burning is a known source of environmental U in the atmosphere. This may partially explain why the U level of our study population was higher compared to some other studies. Fetuses and infants are known to be more sensitive and susceptible to environmental contaminant exposures than adults (Gluckman et al., 2008). Maternal exposures to heavy metals, including As, Pb, Tl and Cd, have previously been associated with increased risks of adverse birth outcomes (Jiang et al., 2018; Odland et al., 1999; Rahman et al., 2009; Yang et al., 2016). In our study, further adjustments for these metals did not significantly alter the correlations of urinary U concentration with adverse birth outcomes, suggesting that the correlations of adverse
3. Results The basic characteristics of the 8500 mother-infant pairs and geometric means of maternal urinary U concentrations according to these characteristics are presented in Table 1. The mean age of the study population was 28.57 ± 3.68 years, with 54.85% of the women between 25 and 29 years old. Among the 8500 participants, 66.24% had a normal pre-pregnancy BMI (18.5–23.9 kg/m2), 81.04% were nulliparous, 3.84% had pregnancy hypertensive disorders, and 9.56% had gestational diabetes mellitus, 24.22% of the mothers reported passive smoking during pregnancy, 68.49% were with college degree or higher. Among the infants, 53.36% were boys, 3.64% were PTB, 2.47% were LBW, and 7.5% were SGA. Urinary U concentrations varied by maternal pre-pregnancy BMI. Women who had higher pre-pregnancy BMI had higher urinary U concentrations. Table 2 shows the distribution of maternal urinary concentrations of U and other metals. All metals were detected in more than 99% of the urinary samples. Both the geometric mean and median values of urinary U concentrations were 0.03 μg/L. The Pearson correlation coefficients of U and other metals ranged from 0.234 to 0.673 (Table S1). Regression coefficients [β (95% CI)] for the correlation between birth outcomes (gestational age, birth weight and birth length) and Log2-U concentration (μg/L) and quartiles of U concentration are presented in Table 3. We observed a significantly negative association between gestational age and Log2-U concentration (adjusted β = −0.23 days, 95% CI: −0.35, −0.12). Compared to the quartile with lowest U, gestational age decreased by 0.16 days (95% CI: −0.64, 0.33) in quartile 2, 0.75 days (95% CI: −1.24, −0.26) in quartile 3, and 1.03 days (95% CI: −1.51, −0.54) in quartile 4 (P for trend < 0.0001). After additional adjustment for other metals, urinary U 3
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Table 1 Geometric mean of urinary U concentrations (μg/L) according to maternal and infant characteristics [n (%)]. Characteristics Age at delivery (years) Mean (SD) < 25 25–29 30–34 ≥35 Pre-pregnancy BMI (kg/m2) < 18.5 18.5–23.9 24.0–27.9 ≥28.0 Missing Parity Nulliparous Multiparous Hypertensive disorders in pregnancy No Yes Gestational diabetes mellitus No Yes Passive smoking during pregnancy No Yes Education Compulsory and lower High school or equivalent Graduate or higher Missing Infant sex Male Female Preterm birth No Yes Low birthweight No Yes Small for gestational age No Yes
All individuals (n = 8500)
GM
Ratio (95% CI)
28.57 (3.68) 891 (10.48) 4662 (54.85) 2365 (27.82) 582 (6.85)
0.033 0.031 0.033 0.034 0.033
1.00 1.08 1.12 1.08
(ref) (0.97, 1.20) (1.00, 1.26) (0.93, 1.27)
1749 (20.58) 5630 (66.24) 917 (10.79) 182 (2.14) 22 (0.26)
0.032 0.033 0.036 0.038 0.031
1.00 1.04 1.19 1.28 0.96
(ref) (0.96, (1.06, (1.02, (0.51,
7141 (84.01) 1359 (15.99)
0.033 0.033
1.00 (ref) 1.03 (0.94, 1.12)
8174 (97.69) 326 (3.84)
0.033 0.034
1.00 (ref) 1.05 (0.89, 1.24)
7687 (90.44) 813 (9.56)
0.033 0.033
1.00 (ref) 1.02 (0.92, 1.14)
6441 (75.78) 2059 (24.22)
0.033 0.032
1.00 (ref) 0.97 (0.90, 1.05)
1081 (12.72) 1595 (18.76) 5822 (68.49) 2 (0.02)
0.034 0.033 0.033 0.018
1.00 0.99 0.95 0.41
4536 (53.36) 3964 (46.64)
0.033 0.033
1.00 (ref) 0.98 (0.92, 1.04)
8191 (96.36) 309 (3.64)
0.033 0.037
1.00 (ref) 1.20 (1.01, 1.42)*
8290 (97.53) 210 (2.47)
0.033 0.030
1.00 (ref) 0.89 (0.73, 1.10)
7791 (91.66) 709 (8.34)
0.033 0.031
1.00 (ref) 0.91 (0.81, 1.02)
1.13) 1.35)* 1.61)* 1.81)
(ref) (0.88, 1.11) (0.86, 1.05) (0.05, 3.27)
Abbreviations: CI, confidence interval; GM, geometric mean; SD, standard deviation; BMI, body-mass index. * P < 0.05.
significantly alter the correlations between urinary U and birth outcomes. Despite these observations, the molecular mechanism underpinning the effect of pregnancy U exposure on these adverse birth outcomes remain to be explored. One of the known effects of U is to alter the cytokine expression profile, such as the upregulation of tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) (Asghari et al., 2015). This has been observed in the serum of U miners (Asghari et al., 2015; Li et al., 2014), and different tissues of mice treated with U, including intestine, testis, and kidney (Asghari et al., 2015; Zheng et al., 2015). Thus, U may similarly induce an inflammatory response in the myometrium to trigger the early onset of chorioamniotic membrane rupture
birth outcomes with concentrations of these metals had little influence on that with urinary U level. Due to the functional impact of pregnancy on kidney physiology, pregnant women often exhibit gestational glomerular hyperfiltration, which leads to a decrease in urinary creatinine (Cheung and Lafayette, 2013). Therefore, to avoid possible bias in this regard, we used urine concentration directly, instead of the creatinine-corrected values, and considered creatinine as a covariate. Furthermore, when excluding mothers with creatinine concentrations below 0.3 g/L or above 3 g/L, significant associations between U exposure and gestational age and PTB remained, indicating that the dynamic changes and individual differences of pregnancy urinary creatinine concentrations did not
Table 2 The distributions of urinary concentrations of U and other metals (μg/L) in the study population. Variable
Uranium Arsenic Lead Cadmium Thallium
No.
8500 8500 8500 8500 8500
GM
0.03 15.23 1.89 0.32 0.27
Percentiles
CV
No. (%)
Per25
Per50
Per75
Intra-day
Inter-day
＞LOD
0.02 8.23 1.24 0.19 0.17
0.03 16.26 2.02 0.33 0.29
0.06 28.63 3.10 0.55 0.48
0.86% 0.55% 0.24% 0.74% 0.80%
2.59% 1.73% 2.45% 2.91% 2.87%
8426 8500 8475 8495 8456
Abbreviations: GM, Geometric mean; CV, coefficient of variance; LOD, limit of detection. 4
(99.13%) (100.00%) (99.71%) (99.94%) (99.48%)
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Table 3 Multivariable linear regression analyses of the associations of maternal urinary U concentrations with gestational age, birth weight and birth length (n = 8500). U levels (μg/L)
Crude β (95% CI)
Adjusted β (95% CI)a
Adjusted β (95% CI)b
Adjusted β (95% CI)c
Gestational age (days) Per unitd Q1 (≤0.02; n = 2125) Q2 (0.02–0.03; n = 2125) Q3 (0.03–0.06; n = 2125) Q4 (> 0.06; n = 2125) P for trende
−0.19 (−0.31, 1.00 (ref) −0.07 (−0.58, −0.56 (−1.07, −0.80 (−1.31, 0.0005
−0.25 (−0.37, 1.00 (ref) −0.26 (−0.77, −0.85 (−1.36, −1.07 (−1.58, < 0.0001
−0.23 (−0.35, 1.00 (ref) −0.16 (−0.64, −0.75 (−1.24, −1.03 (−1.51, < 0.0001
−0.32 (−0.44, 1.00 (ref) −0.33 (−0.82, −0.94 (−1.43, −1.29 (−1.80, < 0.0001
Birth weight (g) Per unitd Q1 (≤0.02; n = 2125) Q2 (0.02–0.03; n = 2125) Q3 (0.03–0.06; n = 2125) Q4 (> 0.06; n = 2125) P for trende
4.19 (−1.92, 10.30) 1.00 (ref) −6.51 (−32.48, 19.46) 3.58 (−22.39, 29.55) 21.29 (−4.68, 47.26) 0.0747
2.11 (−4.05, 8.26) 1.00 (ref) −12.88 (−38.94, 13.17) −6.10 (−32.31, 20.11) 12.54 (−13.62, 38.70) 0.2717
0.60 (−5.37, 6.56) 1.00 (ref) −16.54 (−41.78, 8.70) −12.19 (−37.58, 13.19) 1.11 (−24.24, 26.46) 0.8186
−6.65 (−13.09, −0.20)* 1.00 (ref) −28.53 (−54.01, −3.05)* −27.13 (−52.96, −1.29)* −22.82 (−49.55, 3.91) 0.1301
Birth length (cm) Per unitd Q1 (≤0.02; n = 2125) Q2 (0.02–0.03; n = 2125) Q3 (0.03–0.06; n = 2125) Q4 (> 0.06; n = 2125) P for trende
0.00 (−0.02, 0.03) 1.00 (ref) −0.02 (−0.12, 0.07) 0.02 (−0.07, 0.12) 0.03 (−0.07, 0.13) 0.4219
−0.01 (−0.03, 1.00 (ref) −0.05 (−0.15, −0.02 (−0.11, −0.01 (−0.11, 0.9526
−0.01 (−0.03, 1.00 (ref) −0.06 (−0.16, −0.04 (−0.14, −0.05 (−0.14, 0.5149
−0.03 (−0.06, 1.00 (ref) −0.10 (−0.20, −0.09 (−0.18, −0.12 (−0.22, 0.0508
−0.07)* 0.44) −0.05)* −0.29)*
−0.13)* 0.25) −0.33)* −0.55)*
0.02) 0.05) 0.08) 0.09)
−0.12)* 0.33) −0.26)* −0.54)*
0.01) 0.03) 0.05) 0.05)
−0.20)* 0.15) −0.44)* −0.78)*
−0.01)* 0.00) 0.01) −0.02)*
Abbreviations: CI, confidence interval; Q, quartile. * P < 0.05. a Adjusted for urinary creatinine concentrations (g/L). b Adjusted for urinary creatinine concentrations (g/L), maternal age at delivery, parity, pre-pregnancy BMI, passive smoking, hypertensive disorders in pregnancy, gestational diabetes mellitus, education, and infant gender. Estimates for birth length were also adjusted for paternal height. c Adjusted for urinary creatinine concentrations (g/L), maternal age at delivery, parity, pre-pregnancy BMI, passive smoking, hypertensive disorders in pregnancy, gestational diabetes mellitus, education, infant gender, and urinary concentrations (μg/L) of As, Cd, Tl, and Pb. Estimates for birth length were also adjusted for paternal height. d Per unit increase in the Log2-transformed maternal urinary U concentration (μg/L). e Tests for linear trend were done by modelling the median value of each quartile to test ordered relations across quartiles of urinary U concentrations. Table 4 Risk of birth outcomes associated with maternal urinary U concentrations (n = 8500). U levels (μg/L)
Case (%)
Crude OR (95% CI)
Adjusted OR (95% CI)a
Adjusted OR (95% CI)b
Adjusted OR (95% CI)c
Preterm birth Per unitd Q1 (≤0.02; n = 2125) Q2 (0.02–0.03; n = 2125) Q3 (0.03–0.06; n = 2125) Q4 (> 0.06; n = 2125) P for trende
309 (3.64%) 69 (3.25%) 75 (3.53%) 75 (3.53%) 90 (4.23%)
1.09 (1.01, 1.00 (ref) 1.09 (0.78, 1.09 (0.78, 1.32 (0.96, 0.0941
1.18)*
1.13 (1.04, 1.00 (ref) 1.22 (0.88, 1.29 (0.92, 1.53 (1.11, 0.0100
1.23)*
1.14 (1.05, 1.00 (ref) 1.20 (0.85, 1.28 (0.91, 1.59 (1.15, 0.0052
1.24)*
1.18 (1.07, 1.00 (ref) 1.21 (0.86, 1.30 (0.92, 1.70 (1.20, 0.0028
1.29)*
Low birthweight Per unitd Q1 (≤0.02; n = 2125) Q2 (0.02–0.03; n = 2125) Q3 (0.03–0.06; n = 2125) Q4 (> 0.06; n = 2125) P for trende
210 (2.47%) 54 (2.54%) 58 (2.73%) 51 (2.40%) 47 (2.21%)
0.95 (0.88, 1.00 (ref) 1.08 (0.74, 0.94 (0.64, 0.87 (0.58, 0.3893
1.04)
0.97 (0.89, 1.00 (ref) 1.14 (0.78, 1.03 (0.70, 0.94 (0.63, 0.6535
1.06)
0.97 (0.89, 1.00 (ref) 1.13 (0.77, 1.06 (0.71, 0.99 (0.66, 0.9070
1.07)
1.06 (0.96, 1.00 (ref) 1.30 (0.87, 1.27 (0.84, 1.38 (0.90, 0.1639
1.18)
Small for gestational age Per unitd Q1 (≤0.02; n = 2125) Q2 (0.02–0.03; n = 2125) Q3 (0.03–0.06; n = 2125) Q4 (> 0.06; n = 2125) P for trende
709 194 186 173 156
0.96 (0.91, 1.00 (ref) 0.96 (0.77, 0.88 (0.71, 0.79 (0.63, 0.0258
1.01)
0.97 (0.92, 1.00 (ref) 0.97 (0.79, 0.91 (0.73, 0.81 (0.65, 0.0471
1.01)
0.97 (0.92, 1.00 (ref) 0.99 (0.80, 0.93 (0.75, 0.84 (0.67, 0.0964
1.02)
1.00 (0.94, 1.00 (ref) 1.05 (0.84, 1.00 (0.80, 0.92 (0.72, 0.4219
1.05)
(8.34%) (9.13%) (8.75%) (8.14%) (7.34%)
1.52) 1.52) 1.81)
1.57) 1.39) 1.29)
1.18) 1.09) 0.98)*
1.71) 1.80) 2.11)*
1.67) 1.52) 1.40)
1.20) 1.13) 1.01)
1.69) 1.80) 2.21)*
1.66) 1.57) 1.49)
1.23) 1.16) 1.05)
1.72) 1.85) 2.42)*
1.92) 1.91) 2.12)
1.30) 1.25) 1.16)
Abbreviations: CI, confidence interval; Q, quartile. * P < 0.05. a Adjusted for urinary creatinine concentrations (g/L). b Adjusted for urinary creatinine concentrations (g/L), maternal age at delivery, parity, pre-pregnancy BMI, passive smoking, hypertensive disorders in pregnancy, gestational diabetes mellitus, education, and infant gender. c Adjusted for urinary creatinine concentrations (g/L), maternal age at delivery, parity, pre-pregnancy BMI, passive smoking, hypertensive disorders in pregnancy, gestational diabetes mellitus, education, infant gender, and urinary concentrations (μg/L) of As, Cd, Tl, and Pb. d Per unit increase in the Log2-transformed maternal urinary U concentration (μg/L). e Tests for linear trend were done by modelling the median value of each quartile to test ordered relations across quartiles of urinary U concentrations.
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and uterine contractility, as these events are often accompanied by a switch of pathways from anti-inflammatory to pro-inflammatory signaling (Romero et al., 2014). However, this needs to be validated experimentally, and if true, the responsible inflammatory cytokine(s) should be identified. Our study has several notable strengths. First, the epidemiological study design with a large sample size (8500 mother-singleton pairs) provided an opportunity to evaluate these associations in a well-powered fashion. Second, the interviews, medical records, and other metals concentration provided extensive data on potential confounders. Third, urinary U concentration provided a good reflection of the U body burden to assess the levels of maternal exposure (Keith et al., 2013). Forth, the impact of other known harmful heavy metals on birth outcomes were taken into consideration. On the other hand, the present study also has a few limitations. For instance, we only measured urinary U at a single time point before delivery, which may not accurately reflect the U exposure throughout the course of pregnancy. Also, we were unable to determine the critical windows of prenatal U exposure that possibly increased the risk of adverse birth outcomes. Lastly, we failed to evaluate the association between paternal U exposure and birth outcomes because of the lacking of paternal samples. In summary, we observed significant correlations between prenatal exposure to U and decreased gestational age and increased risk of PTB in this large birth cohort. These results suggested that maternal U exposure during pregnancy may lead to adverse birth outcomes. From a public health perspective, our study highlights the urgency for strategic intervention to reduce the risk of U exposure during pregnancy.
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Prediction of small for gestational age infants in healthy nulliparous women using clinical and ultrasound risk factors combined with early pregnancy biomarkers. PLoS One 12, e0169311. Moster, D., Lie, R.T., Markestad, T., 2008. Long-term medical and social consequences of preterm birth. New Engl. J. Med. 359, 262–273. Odland, J.O., Nieboer, E., Romanova, N., Thomassen, Y., Lund, E., 1999. Blood lead and cadmium and birth weight among sub-arctic and arctic populations of Norway and Russia. Acta Obstet. Gynecol. Scand. 78, 852–860. Orloff, K.G., Mistry, K., Charp, P., Metcalf, S., Marino, R., Shelly, T., Melaro, E., Donohoe, A.M., Jones, R.L., 2004. Human exposure to uranium in groundwater. Environ. Res. 94, 319–326. Paternain, J.L., Domingo, J.L., Ortega, A., Llobet, J.M., 1989. The effects of uranium on reproduction, gestation, and postnatal survival in mice. Ecotoxicol. Environ. Saf. 17, 291–296. 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Declaration of Competing Interest The authors declare no conflict of interest pertain to this work. Acknowledgments We thank all the participants in the study and all collaborators in the study hospital. This work was supported by the National Natural Science Foundation of China (91643207, 21437002 and 91743101); National Key Research and Development Plan of China (2016YFC0206203 and 2016YFC0206700); Fundamental Research Funds for the Central Universities, Huazhong University of Science and Technology (2016YXZD043); and Talent Introduction Fund, Huazhong University of Science and Technology (3004513124). Appendix A. Supplementary material Supplementary data to this article can be found online at https:// doi.org/10.1016/j.envint.2019.105391. References JAMA patient page, 2002. Low birth weight. JAMA 287, 270. Aakre, I., Henjum, S., Folven Gjengedal, E. L., Risa Haugstad, C., Vollset, M., Moubarak, K., Saleh Ahmed, T., Alexander, J., Kjellevold, M., and Molin, M. (2018). Trace Element Concentrations in Drinking Water and Urine among Saharawi Women and Young Children. Toxics 6. Ahmad, S.A., Sayed, M.H., Barua, S., Khan, M.H., Faruquee, M.H., Jalil, A., Hadi, S.A., Talukder, H.K., 2001. Arsenic in drinking water and pregnancy outcomes. Environ. Health Perspect. 109, 629–631. Asghari, M.H., Saeidnia, S., Rezvanfar, M.A., Abdollahi, M., 2015. A systematic review of the molecular mechanisms of uranium -induced reproductive toxicity. Inflamm. Allergy Drug Targets 14, 67–76. Bloom, M.S., Buck Louis, G.M., Sundaram, R., Maisog, J.M., Steuerwald, A.J., Parsons, P.J., 2015. Birth outcomes and background exposures to select elements, the Longitudinal Investigation of Fertility and the Environment (LIFE). Environ. Res. 138, 118–129. Boumans, P.W.J.M., Ivaldi, J., Slavin, W., 1991. Measuring detection limits in inductively coupled plasma emission spectrometry using the “SBR—RSDB approach”—I. A tutorial discussion of the theory. Spectrochim. Acta Part B 46, 431–445. Callan, A.C., Hinwood, A.L., Ramalingam, M., Boyce, M., Heyworth, J., McCafferty, P., Odland, J.O., 2013. Maternal exposure to metals–concentrations and predictors of
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Association of adverse birth outcomes with prenatal uranium exposure: A population-based cohort study
T
Weiping Zhanga,1, Wenyu Liua,1, Shuangshuang Baoa, Hongxiu Liua, Yuzeng Zhanga, Bin Zhangb, ⁎ ⁎ Aifen Zhoub, Jia Chenc, Ke Haod, Wei Xiaa, Yuanyuan Lia, Xia Shenga, , Shunqing Xua, a Key Laboratory of Environment and Health (HUST), Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China b Wuhan Women and Children Medical Care Center, Wuhan, Hubei, China c Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA d Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
A R T I C LE I N FO
A B S T R A C T
Handling Editor: Mark Nieuwenhuijsen
Uranium (U) is a well-recognized hazardous heavy metal with embryotoxicity and fetotoxicity. However, little is known about its association with adverse birth outcomes. We aimed to investigate the potential correlation between prenatal U exposure and birth outcomes. Urine samples of 8500 women were collected before delivery from a birth cohort in Wuhan, China. Concentrations of urinary U and other metals were measured by inductively coupled plasma mass spectrometry. We used multivariable logistic regressions to evaluate the associations between urinary U concentrations and adverse birth outcomes, such as preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA). Associations of urinary U concentrations with gestational age, birth weight, and birth length were investigated by linear regressions. The geometric mean of U concentration was 0.03 μg/L. After adjustment for potential confounders, we found each Log2-unit increase in U concentration was associated with a significant decrease in gestational age [adjusted β = −0.32 day; 95% confidence interval (CI): −0.44, −0.20] and a significant increased likelihood of PTB (adjusted OR = 1.18, 95% CI: 1.07, 1.29). This birth cohort uncovered an association of maternal exposure to U during pregnancy with decreased gestational age and increased risk of PTB. Our findings reveal an association of maternal exposure to U during pregnancy with decreased gestational age and increased risk of PTB.
Keywords: Adverse birth outcomes Gestational age Prenatal exposure Preterm birth Uranium
1. Introduction Uranium (U) is a heavy metal with both chemical toxicity and radioactivity. In the environment, U can be detected in rocks, soil and groundwater, with the 238U being the most common isotope of the element (> 99.27%) (Domingo, 2001). In recent decades, U has been widely used in nuclear power reactors and nuclear weapons, which has also led to environmental pollution and serious health safety concerns. Similar to many other heavy metals, there are mainly two types of U exposure, acute high-level exposure due to occupational reasons, and chronic low-dose exposure for the general population either by inhalation or by dietary intake (Keith et al., 2013; May et al., 2004). U can enter the human body via air, food or drinking water, where it is taken up in the blood (Keith et al., 2013; Selden et al., 2009). Approximately 67% of U in the blood is filtered in the kidneys and leaves
the body in urine, with a half-life between 12 and 24 h, providing a rationale for measuring U exposure by urinalysis (May et al., 2004). U exposure can cause significant renal damage, but the toxic effect is not restricted to the kidney. A number of recent animal studies have shown that adulthood U exposure affect the function of various organs, including the intestine, reproductive system, and brain (Dublineau et al., 2007; Feugier et al., 2008; Legendre et al., 2016; Lestaevel et al., 2005). In particular, high dose of maternal U exposure during pregnancy could cause developmental toxicity in fetuses in mice (Domingo et al., 1989; Paternain et al., 1989). However, detailed molecular mechanism underlying these phenomena is not fully understood. Adverse birth outcomes, such as preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA) represent significant health problems across the globe. PTB, defined as birth occurring before 37 completed weeks of gestation, is the leading contributor to neonatal
⁎
Corresponding authors. E-mail addresses: [email protected] (X. Sheng), [email protected] (S. Xu). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.envint.2019.105391 Received 29 August 2019; Received in revised form 10 October 2019; Accepted 3 December 2019 0160-4120/ © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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Urine (SRM2670a Toxic Elements in Urine; National Institute of Standards and Technology, Gaithersburg, MD, USA) was used as an external quality-control sample in each batch to improve the accuracy of the measurements, and the concentrations measured were within the certified range. LOD was determined according to the previously described equation LOD = 3RSDb × C/SBR (Boumans et al., 1991). The limit of detection (LOD) for U was 1.5 × 10−4 μg/L. The recovery of the quality control standard by using this procedure was 99.75%. The intra-day coefficient of variation (CV) was 0.86%, and inter-day CV was 2.59%. Urine creatinine concentrations were measured by a creatinine kit (Mindray BS-200 CREA Kit, Shenzhen Mindray Bio-medical Electronics Co., Ltd).
death (Frey and Klebanoff, 2016). Its potential adverse impact may extend to later life periods on medical, psychological, behavioral and social aspects (Moster et al., 2008). LBW infants, weighing less than 2500 g at (2002), display a 25-fold increase in mortality rate relative to their normal counterparts (Mathews and MacDorman, 2008). SGA babies normally refer to those whose birth weights are below the 10th percentile for the gestational age. They are possibly at increased risk of cardiovascular disease and diabetes in adulthood (McCowan et al., 2010; McCowan et al., 2017). Recent epidemiological studies from us and others have suggested that maternal environmental exposures to heavy metals, such as lead (Pb), arsenic (As), cadmium (Cd) and thallium (Tl), are associated with increased risks of various adverse birth outcomes, including PTB, SGA and LBW (Jiang et al., 2018; Odland et al., 1999; Rahman et al., 2009; Yang et al., 2016). Despite the known toxicity of U, Bloom et al. failed to observe an association of maternal urinary U concentration with birth size and gestational age, instead they found that higher paternal urinary U level was correlated with lower birth weight and shorter birth length (Bloom et al., 2015). Therefore, whether maternal U exposure during pregnancy has an effect on birth outcomes remains to be characterized. To this end, taking advantage of a large birth cohort in Wuhan, China, the present study aimed to investigate the correlations between prenatal U exposure and the risk of adverse birth outcomes, including PTB, LBW, SGA and other birth outcomes, such as gestational age, birth weight and birth length.
2.3. Data collection Face to face interviews were conducted by well-trained interviewers within three days before or after delivery to collect maternal sociodemographic characteristics and life style factors, including maternal age, occupational status, education background, tobacco use, passive smoking and alcohol consumption. Information on pregnancy complications, parity, fetal sex, birth weight and birth length were obtained from medical records. Gestational age was calculated based on ultrasound measurements in the first trimester. The pre-pregnancy BMI was calculated using pre-pregnancy body weight and height. Pre-pregnancy body weight was self-reported and height was measured using a stadiometer in hospital. Additionally, pre-pregnancy BMI was categorized into four classes based on the Chinese standard (underweight: < 18.5 kg/m2, normal: 18.5–23.9 kg/m2, overweight: 23.9–27.9 kg/m2, and obese: ≥28.0 kg/m2) (Zhou et al., 2002).
2. Methods 2.1. Study population The present study was a part of a prospective birth cohort study that recruited pregnant women in Wuhan Women and Children’s Medical Care Center from 2012 to 2014 in Wuhan, China. Pregnant women who met the following criteria were recruited: (a) with a singleton gestation and live birth; (b) resident of Wuhan City; (c) ability to comprehend the Chinese language without communication problem. All participants provided written informed consent at enrollment. Ethical approval for the study was approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology, and Wuhan Women and Children’s Medical Care Center. During September 2012 and October 2014, we enrolled 8565 pregnant women with spot urine samples. Women who gave birth to an infant with a birth defect were excluded (n = 65), leaving the final analysis with 8,500 mother-infant pairs.
2.4. Study outcomes The study outcomes include adverse birth outcomes (PTB, LBW and SGA), gestational age, birth weight and birth length. PTB was defined as babies born alive before 37 weeks of pregnancy are completed. LBW was referred to a birth weight less than 2500 g. SGA was defined as a birth weight below the 10th percentile for the gestational age by infant sex based on all the newborns in our birth cohort from Wuhan. 2.5. Statistical analysis For analysis, values for U concentrations below the LOD was replaced by one-half LOD (Harel et al., 2014). As the Shapiro-Wilk normality test showed that the urinary metal concentrations were highly skewed, the geometric mean and percentiles of urinary metal concentrations were calculated, and Log2 transformations of the values were applied for urinary metal concentrations before analyses. We next examined the association between urinary U levels and sociodemographic characteristics using general linear models. Beta coefficients from the general linear models were exponentiated to produce the ratio of urinary U levels between different categories of demo-socioeconomic characteristics. The values above or below 1.0 means that urinary U concentrations were respectively higher or lower in that category compared to the reference category. In addition, we calculated Pearson correlation coefficients using Log2-transformed concentrations of metals. We used linear regression models to estimate the association of Log2-transformed urinary U concentrations (Log2-U, as a continuous variable) with continuous birth outcomes (gestational age, birth weight and birth length). Logistic regression models were also performed to assess the association of Log2-transformed urinary U concentrations (Log2-U, as a continuous variable) with the risk of birth outcomes (PTB, LBW and SGA). To test potential non-linear dose-response relationship, we also assessed the association between U concentration quartiles (as a categorical variable, and the lowest quartile was assigned as the reference)
2.2. Urine sample collection and U measurements Spot urine samples were collected from pregnant women immediately after they were admitted to the hospital for delivery (within 3 days prior to delivery). Urine samples were stored in the 5 mL polypropylene tubes at −20 °C until further analysis. Inductively coupled plasma mass spectrometry (ICP-MS) (Agilent 7700, Agilent Technologies) was used to analyze the urinary U concentrations. Urine samples were first thawed at room temperature (20–25 °C). After being thoroughly vortexed, they were added into 15 mL polypropylene tubes with 1.2% (v/v) nitric acid (HNO3) for overnight nitrification. Next, the resulting samples were digested by ultrasound at 40 °C for one hour, and U was measured by ICP-MS. Urinary total arsenic (As), lead (Pb), thallium (Tl) and cadmium (Cd) levels were also measured by the same method. The operating parameters for ICP-MS were as follows: radio frequency power 1550 W, plasma gas flow 15.00 L/min, auxiliary gas flow 0.8 L/min, carrier gas flow 0.8 L/min, resolution (peak high 10%) 0.65–0.80 amu, sample uptake rate 0.4 mL/min, unimodal residence time 0.30 s (0.99 s for Cd), repetitions 3 times. Stringent laboratory quality controls were implemented to ensure the accuracy of the analyses. The Standard Reference Material Human 2
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concentrations remained inversely associated with gestational age and the associations became slightly stronger. Moreover, birth weight (adjusted β = 0.60 g, 95% CI: −5.37, 6.56) and birth length (adjusted β = −0.01 cm; 95% CI: −0.03, 0.01) were not associated with urinary U concentrations. But after additional adjustment for other metals, significant association of U with birth weight [adjusted β = −6.65 g, 95% CI: −13.09, −0.20; quartile 1 = 1; quartile 2 = −28.53 (95% CI: −54.01, −3.05); quartile 3 = −27.13 (95% CI: −52.96, −1.29); quartile 4 = −22.82 (95% CI: −49.55, 3.91); P for trend = 0.1301] and birth length [adjusted β = −0.03 cm, 95% CI:−0.06, −0.01; quartile 1 = 1; quartile 2 = −0.10 (95% CI: −0.20, 0.00); quartile 3 = −0.09 (95% CI: −0.18, 0.01); quartile 4 = −0.12 (95% CI: −0.22, −0.02); P for trend = 0.0508] was found. The odds ratios (ORs) and 95% CIs for adverse birth outcomes including PTB, LBW and SGA according to maternal urinary U concentrations (μg/L) are shown in Table 4. The adjusted OR for per unit increase in Log2-U concentrations was 1.14 (95% CI: 1.05, 1.24) for PTB. Women who were in the highest quartile of U concentration (urinary U concentrations > 0.06 μg/L) displayed about 1.59 fold increased risk of preterm delivery (adjusted OR: 1.59, 95% CI: 1.15, 2.21, P for trend: 0.0052) compared with women who were in the lowest quartile (urinary U concentrations < 0.02 μg/L). After additional adjustment for other metals, the ORs of PTB for increase in Log2-U concentrations became slightly higher. In addition, maternal urinary U concentrations was not significantly correlated with the likelihood of LBW (adjusted OR: 0.97, 95% CI: 0.89, 1.07) and SGA (adjusted OR: 0.97, 95% CI: 0.92, 1.02). Lastly, in the sensitivity analyses excluding mothers with creatinine concentrations below 0.3 g/L or above 3 g/L (6286 mother-infant pairs included), the association of urinary U concentration with birth outcomes were similar to the results of primary analyses (Tables S2 and S3).
and birth outcomes using regression models described above. Tests for linear trend were conducted by modeling the median value of each quartile to test ordered relations across quartiles of urinary U concentrations. All multivariate regression models were adjusted for maternal age (< 25 y, 25–29 y, 30–34 y, ≥35 y), maternal education (compulsory or lower, high school or equivalent, graduate or higher), parity (nulliparous, multiparous), pre-pregnancy BMI (< 18.5 kg/m2, 18.5–23.9 kg/m2, 23.9–27.9 kg/m2, ≥28.0 kg/m2), passive smoking, hypertensive disorders in pregnancy, gestational diabetes mellitus, fetal sex and paternal height (in birth length models). We chose these potential confounders for being previously reported to associate with birth outcomes or U exposures, or if they resulted in a > 10% change in the main effect estimates. Furthermore, as previous studies from ours (using the same cohort) as well as others have associated As, Pb, Tl and Cd with adverse birth outcomes (Ahmad et al., 2001; Cheng et al., 2017; Jiang et al., 2018; Yang et al., 2016), we also adjusted all regression models for urinary total As, Pb, Tl and Cd. Except for paternal height, and urinary concentrations of total As, Pb, Tl and Cd, all the potential confounders were categorical variables. Owing to the low rates of maternal smoking (9/ 8500, 0.11%) and alcohol use (2/8500, 0.02%) during pregnancy in this cohort, these factors were not adjusted for. Missing values of categorical variable were grouped into another category to avoid losing samples due to missing values of confounders. Due to the functional impact of pregnancy on kidney physiology, pregnant women often exhibit gestational glomerular hyperfiltration, which leads to an expected decrease in urinary creatinine (Cheung and Lafayette, 2013). Thus, we entered creatinine as a covariate instead of using creatinine-corrected U concentrations to accommodate urine dilution. To further rule out the possible impact in this regard, we also conducted a sensitivity analysis only including women with urinary creatinine concentrations between 0.3 g/L and 3.0 g/L (n = 6286). Statistical analyses were performed using SAS (version9.4; SAS Institute Inc.). Two-sided p < 0.05 was considered statistically significant.
4. Discussion This prenatal cohort study investigated the associations of U exposure with birth outcomes in a large population of 8500 women recruited in Wuhan, China. Based on the measurement of urinary U concentrations shortly prior to delivery, we observed significant associations of increased prenatal urinary U concentration with shortened gestational age and higher risk of PTB. For most people, ingestion is the most common pathway of exposure to U, and the absorbed U is excreted in urine mostly as uranyl ions, thus the exposure level can be determined by measuring the urinary U concentration (Keith et al., 2013; Selden et al., 2009). In this study, U was detected in 99.13% of the maternal urine samples, indicating that our study population was widely exposed to U, at least during pregnancy. Comparatively, the urinary U concentrations in our study (GM, 0.03 μg/L; median, 0.03 μg/L) was higher than those of pregnant women in Australia (GM, 0.013 μg/L; median, 0.005 μg/L) and USA (GM, 0.006 μg/L) (Callan et al., 2013; Jain, 2013), but lower than those of the general population in Saharawi (median, 0.15 μg/L) and South Carolina (median, 0.162 μg/L) (Aakre et al., 2018; Orloff et al., 2004). Wuhan is a major heavy industry city in Central China with many coalfired power plants and steelworks, and coal burning is a known source of environmental U in the atmosphere. This may partially explain why the U level of our study population was higher compared to some other studies. Fetuses and infants are known to be more sensitive and susceptible to environmental contaminant exposures than adults (Gluckman et al., 2008). Maternal exposures to heavy metals, including As, Pb, Tl and Cd, have previously been associated with increased risks of adverse birth outcomes (Jiang et al., 2018; Odland et al., 1999; Rahman et al., 2009; Yang et al., 2016). In our study, further adjustments for these metals did not significantly alter the correlations of urinary U concentration with adverse birth outcomes, suggesting that the correlations of adverse
3. Results The basic characteristics of the 8500 mother-infant pairs and geometric means of maternal urinary U concentrations according to these characteristics are presented in Table 1. The mean age of the study population was 28.57 ± 3.68 years, with 54.85% of the women between 25 and 29 years old. Among the 8500 participants, 66.24% had a normal pre-pregnancy BMI (18.5–23.9 kg/m2), 81.04% were nulliparous, 3.84% had pregnancy hypertensive disorders, and 9.56% had gestational diabetes mellitus, 24.22% of the mothers reported passive smoking during pregnancy, 68.49% were with college degree or higher. Among the infants, 53.36% were boys, 3.64% were PTB, 2.47% were LBW, and 7.5% were SGA. Urinary U concentrations varied by maternal pre-pregnancy BMI. Women who had higher pre-pregnancy BMI had higher urinary U concentrations. Table 2 shows the distribution of maternal urinary concentrations of U and other metals. All metals were detected in more than 99% of the urinary samples. Both the geometric mean and median values of urinary U concentrations were 0.03 μg/L. The Pearson correlation coefficients of U and other metals ranged from 0.234 to 0.673 (Table S1). Regression coefficients [β (95% CI)] for the correlation between birth outcomes (gestational age, birth weight and birth length) and Log2-U concentration (μg/L) and quartiles of U concentration are presented in Table 3. We observed a significantly negative association between gestational age and Log2-U concentration (adjusted β = −0.23 days, 95% CI: −0.35, −0.12). Compared to the quartile with lowest U, gestational age decreased by 0.16 days (95% CI: −0.64, 0.33) in quartile 2, 0.75 days (95% CI: −1.24, −0.26) in quartile 3, and 1.03 days (95% CI: −1.51, −0.54) in quartile 4 (P for trend < 0.0001). After additional adjustment for other metals, urinary U 3
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Table 1 Geometric mean of urinary U concentrations (μg/L) according to maternal and infant characteristics [n (%)]. Characteristics Age at delivery (years) Mean (SD) < 25 25–29 30–34 ≥35 Pre-pregnancy BMI (kg/m2) < 18.5 18.5–23.9 24.0–27.9 ≥28.0 Missing Parity Nulliparous Multiparous Hypertensive disorders in pregnancy No Yes Gestational diabetes mellitus No Yes Passive smoking during pregnancy No Yes Education Compulsory and lower High school or equivalent Graduate or higher Missing Infant sex Male Female Preterm birth No Yes Low birthweight No Yes Small for gestational age No Yes
All individuals (n = 8500)
GM
Ratio (95% CI)
28.57 (3.68) 891 (10.48) 4662 (54.85) 2365 (27.82) 582 (6.85)
0.033 0.031 0.033 0.034 0.033
1.00 1.08 1.12 1.08
(ref) (0.97, 1.20) (1.00, 1.26) (0.93, 1.27)
1749 (20.58) 5630 (66.24) 917 (10.79) 182 (2.14) 22 (0.26)
0.032 0.033 0.036 0.038 0.031
1.00 1.04 1.19 1.28 0.96
(ref) (0.96, (1.06, (1.02, (0.51,
7141 (84.01) 1359 (15.99)
0.033 0.033
1.00 (ref) 1.03 (0.94, 1.12)
8174 (97.69) 326 (3.84)
0.033 0.034
1.00 (ref) 1.05 (0.89, 1.24)
7687 (90.44) 813 (9.56)
0.033 0.033
1.00 (ref) 1.02 (0.92, 1.14)
6441 (75.78) 2059 (24.22)
0.033 0.032
1.00 (ref) 0.97 (0.90, 1.05)
1081 (12.72) 1595 (18.76) 5822 (68.49) 2 (0.02)
0.034 0.033 0.033 0.018
1.00 0.99 0.95 0.41
4536 (53.36) 3964 (46.64)
0.033 0.033
1.00 (ref) 0.98 (0.92, 1.04)
8191 (96.36) 309 (3.64)
0.033 0.037
1.00 (ref) 1.20 (1.01, 1.42)*
8290 (97.53) 210 (2.47)
0.033 0.030
1.00 (ref) 0.89 (0.73, 1.10)
7791 (91.66) 709 (8.34)
0.033 0.031
1.00 (ref) 0.91 (0.81, 1.02)
1.13) 1.35)* 1.61)* 1.81)
(ref) (0.88, 1.11) (0.86, 1.05) (0.05, 3.27)
Abbreviations: CI, confidence interval; GM, geometric mean; SD, standard deviation; BMI, body-mass index. * P < 0.05.
significantly alter the correlations between urinary U and birth outcomes. Despite these observations, the molecular mechanism underpinning the effect of pregnancy U exposure on these adverse birth outcomes remain to be explored. One of the known effects of U is to alter the cytokine expression profile, such as the upregulation of tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) (Asghari et al., 2015). This has been observed in the serum of U miners (Asghari et al., 2015; Li et al., 2014), and different tissues of mice treated with U, including intestine, testis, and kidney (Asghari et al., 2015; Zheng et al., 2015). Thus, U may similarly induce an inflammatory response in the myometrium to trigger the early onset of chorioamniotic membrane rupture
birth outcomes with concentrations of these metals had little influence on that with urinary U level. Due to the functional impact of pregnancy on kidney physiology, pregnant women often exhibit gestational glomerular hyperfiltration, which leads to a decrease in urinary creatinine (Cheung and Lafayette, 2013). Therefore, to avoid possible bias in this regard, we used urine concentration directly, instead of the creatinine-corrected values, and considered creatinine as a covariate. Furthermore, when excluding mothers with creatinine concentrations below 0.3 g/L or above 3 g/L, significant associations between U exposure and gestational age and PTB remained, indicating that the dynamic changes and individual differences of pregnancy urinary creatinine concentrations did not
Table 2 The distributions of urinary concentrations of U and other metals (μg/L) in the study population. Variable
Uranium Arsenic Lead Cadmium Thallium
No.
8500 8500 8500 8500 8500
GM
0.03 15.23 1.89 0.32 0.27
Percentiles
CV
No. (%)
Per25
Per50
Per75
Intra-day
Inter-day
＞LOD
0.02 8.23 1.24 0.19 0.17
0.03 16.26 2.02 0.33 0.29
0.06 28.63 3.10 0.55 0.48
0.86% 0.55% 0.24% 0.74% 0.80%
2.59% 1.73% 2.45% 2.91% 2.87%
8426 8500 8475 8495 8456
Abbreviations: GM, Geometric mean; CV, coefficient of variance; LOD, limit of detection. 4
(99.13%) (100.00%) (99.71%) (99.94%) (99.48%)
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Table 3 Multivariable linear regression analyses of the associations of maternal urinary U concentrations with gestational age, birth weight and birth length (n = 8500). U levels (μg/L)
Crude β (95% CI)
Adjusted β (95% CI)a
Adjusted β (95% CI)b
Adjusted β (95% CI)c
Gestational age (days) Per unitd Q1 (≤0.02; n = 2125) Q2 (0.02–0.03; n = 2125) Q3 (0.03–0.06; n = 2125) Q4 (> 0.06; n = 2125) P for trende
−0.19 (−0.31, 1.00 (ref) −0.07 (−0.58, −0.56 (−1.07, −0.80 (−1.31, 0.0005
−0.25 (−0.37, 1.00 (ref) −0.26 (−0.77, −0.85 (−1.36, −1.07 (−1.58, < 0.0001
−0.23 (−0.35, 1.00 (ref) −0.16 (−0.64, −0.75 (−1.24, −1.03 (−1.51, < 0.0001
−0.32 (−0.44, 1.00 (ref) −0.33 (−0.82, −0.94 (−1.43, −1.29 (−1.80, < 0.0001
Birth weight (g) Per unitd Q1 (≤0.02; n = 2125) Q2 (0.02–0.03; n = 2125) Q3 (0.03–0.06; n = 2125) Q4 (> 0.06; n = 2125) P for trende
4.19 (−1.92, 10.30) 1.00 (ref) −6.51 (−32.48, 19.46) 3.58 (−22.39, 29.55) 21.29 (−4.68, 47.26) 0.0747
2.11 (−4.05, 8.26) 1.00 (ref) −12.88 (−38.94, 13.17) −6.10 (−32.31, 20.11) 12.54 (−13.62, 38.70) 0.2717
0.60 (−5.37, 6.56) 1.00 (ref) −16.54 (−41.78, 8.70) −12.19 (−37.58, 13.19) 1.11 (−24.24, 26.46) 0.8186
−6.65 (−13.09, −0.20)* 1.00 (ref) −28.53 (−54.01, −3.05)* −27.13 (−52.96, −1.29)* −22.82 (−49.55, 3.91) 0.1301
Birth length (cm) Per unitd Q1 (≤0.02; n = 2125) Q2 (0.02–0.03; n = 2125) Q3 (0.03–0.06; n = 2125) Q4 (> 0.06; n = 2125) P for trende
0.00 (−0.02, 0.03) 1.00 (ref) −0.02 (−0.12, 0.07) 0.02 (−0.07, 0.12) 0.03 (−0.07, 0.13) 0.4219
−0.01 (−0.03, 1.00 (ref) −0.05 (−0.15, −0.02 (−0.11, −0.01 (−0.11, 0.9526
−0.01 (−0.03, 1.00 (ref) −0.06 (−0.16, −0.04 (−0.14, −0.05 (−0.14, 0.5149
−0.03 (−0.06, 1.00 (ref) −0.10 (−0.20, −0.09 (−0.18, −0.12 (−0.22, 0.0508
−0.07)* 0.44) −0.05)* −0.29)*
−0.13)* 0.25) −0.33)* −0.55)*
0.02) 0.05) 0.08) 0.09)
−0.12)* 0.33) −0.26)* −0.54)*
0.01) 0.03) 0.05) 0.05)
−0.20)* 0.15) −0.44)* −0.78)*
−0.01)* 0.00) 0.01) −0.02)*
Abbreviations: CI, confidence interval; Q, quartile. * P < 0.05. a Adjusted for urinary creatinine concentrations (g/L). b Adjusted for urinary creatinine concentrations (g/L), maternal age at delivery, parity, pre-pregnancy BMI, passive smoking, hypertensive disorders in pregnancy, gestational diabetes mellitus, education, and infant gender. Estimates for birth length were also adjusted for paternal height. c Adjusted for urinary creatinine concentrations (g/L), maternal age at delivery, parity, pre-pregnancy BMI, passive smoking, hypertensive disorders in pregnancy, gestational diabetes mellitus, education, infant gender, and urinary concentrations (μg/L) of As, Cd, Tl, and Pb. Estimates for birth length were also adjusted for paternal height. d Per unit increase in the Log2-transformed maternal urinary U concentration (μg/L). e Tests for linear trend were done by modelling the median value of each quartile to test ordered relations across quartiles of urinary U concentrations. Table 4 Risk of birth outcomes associated with maternal urinary U concentrations (n = 8500). U levels (μg/L)
Case (%)
Crude OR (95% CI)
Adjusted OR (95% CI)a
Adjusted OR (95% CI)b
Adjusted OR (95% CI)c
Preterm birth Per unitd Q1 (≤0.02; n = 2125) Q2 (0.02–0.03; n = 2125) Q3 (0.03–0.06; n = 2125) Q4 (> 0.06; n = 2125) P for trende
309 (3.64%) 69 (3.25%) 75 (3.53%) 75 (3.53%) 90 (4.23%)
1.09 (1.01, 1.00 (ref) 1.09 (0.78, 1.09 (0.78, 1.32 (0.96, 0.0941
1.18)*
1.13 (1.04, 1.00 (ref) 1.22 (0.88, 1.29 (0.92, 1.53 (1.11, 0.0100
1.23)*
1.14 (1.05, 1.00 (ref) 1.20 (0.85, 1.28 (0.91, 1.59 (1.15, 0.0052
1.24)*
1.18 (1.07, 1.00 (ref) 1.21 (0.86, 1.30 (0.92, 1.70 (1.20, 0.0028
1.29)*
Low birthweight Per unitd Q1 (≤0.02; n = 2125) Q2 (0.02–0.03; n = 2125) Q3 (0.03–0.06; n = 2125) Q4 (> 0.06; n = 2125) P for trende
210 (2.47%) 54 (2.54%) 58 (2.73%) 51 (2.40%) 47 (2.21%)
0.95 (0.88, 1.00 (ref) 1.08 (0.74, 0.94 (0.64, 0.87 (0.58, 0.3893
1.04)
0.97 (0.89, 1.00 (ref) 1.14 (0.78, 1.03 (0.70, 0.94 (0.63, 0.6535
1.06)
0.97 (0.89, 1.00 (ref) 1.13 (0.77, 1.06 (0.71, 0.99 (0.66, 0.9070
1.07)
1.06 (0.96, 1.00 (ref) 1.30 (0.87, 1.27 (0.84, 1.38 (0.90, 0.1639
1.18)
Small for gestational age Per unitd Q1 (≤0.02; n = 2125) Q2 (0.02–0.03; n = 2125) Q3 (0.03–0.06; n = 2125) Q4 (> 0.06; n = 2125) P for trende
709 194 186 173 156
0.96 (0.91, 1.00 (ref) 0.96 (0.77, 0.88 (0.71, 0.79 (0.63, 0.0258
1.01)
0.97 (0.92, 1.00 (ref) 0.97 (0.79, 0.91 (0.73, 0.81 (0.65, 0.0471
1.01)
0.97 (0.92, 1.00 (ref) 0.99 (0.80, 0.93 (0.75, 0.84 (0.67, 0.0964
1.02)
1.00 (0.94, 1.00 (ref) 1.05 (0.84, 1.00 (0.80, 0.92 (0.72, 0.4219
1.05)
(8.34%) (9.13%) (8.75%) (8.14%) (7.34%)
1.52) 1.52) 1.81)
1.57) 1.39) 1.29)
1.18) 1.09) 0.98)*
1.71) 1.80) 2.11)*
1.67) 1.52) 1.40)
1.20) 1.13) 1.01)
1.69) 1.80) 2.21)*
1.66) 1.57) 1.49)
1.23) 1.16) 1.05)
1.72) 1.85) 2.42)*
1.92) 1.91) 2.12)
1.30) 1.25) 1.16)
Abbreviations: CI, confidence interval; Q, quartile. * P < 0.05. a Adjusted for urinary creatinine concentrations (g/L). b Adjusted for urinary creatinine concentrations (g/L), maternal age at delivery, parity, pre-pregnancy BMI, passive smoking, hypertensive disorders in pregnancy, gestational diabetes mellitus, education, and infant gender. c Adjusted for urinary creatinine concentrations (g/L), maternal age at delivery, parity, pre-pregnancy BMI, passive smoking, hypertensive disorders in pregnancy, gestational diabetes mellitus, education, infant gender, and urinary concentrations (μg/L) of As, Cd, Tl, and Pb. d Per unit increase in the Log2-transformed maternal urinary U concentration (μg/L). e Tests for linear trend were done by modelling the median value of each quartile to test ordered relations across quartiles of urinary U concentrations.
5
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and uterine contractility, as these events are often accompanied by a switch of pathways from anti-inflammatory to pro-inflammatory signaling (Romero et al., 2014). However, this needs to be validated experimentally, and if true, the responsible inflammatory cytokine(s) should be identified. Our study has several notable strengths. First, the epidemiological study design with a large sample size (8500 mother-singleton pairs) provided an opportunity to evaluate these associations in a well-powered fashion. Second, the interviews, medical records, and other metals concentration provided extensive data on potential confounders. Third, urinary U concentration provided a good reflection of the U body burden to assess the levels of maternal exposure (Keith et al., 2013). Forth, the impact of other known harmful heavy metals on birth outcomes were taken into consideration. On the other hand, the present study also has a few limitations. For instance, we only measured urinary U at a single time point before delivery, which may not accurately reflect the U exposure throughout the course of pregnancy. Also, we were unable to determine the critical windows of prenatal U exposure that possibly increased the risk of adverse birth outcomes. Lastly, we failed to evaluate the association between paternal U exposure and birth outcomes because of the lacking of paternal samples. In summary, we observed significant correlations between prenatal exposure to U and decreased gestational age and increased risk of PTB in this large birth cohort. These results suggested that maternal U exposure during pregnancy may lead to adverse birth outcomes. From a public health perspective, our study highlights the urgency for strategic intervention to reduce the risk of U exposure during pregnancy.
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Declaration of Competing Interest The authors declare no conflict of interest pertain to this work. Acknowledgments We thank all the participants in the study and all collaborators in the study hospital. This work was supported by the National Natural Science Foundation of China (91643207, 21437002 and 91743101); National Key Research and Development Plan of China (2016YFC0206203 and 2016YFC0206700); Fundamental Research Funds for the Central Universities, Huazhong University of Science and Technology (2016YXZD043); and Talent Introduction Fund, Huazhong University of Science and Technology (3004513124). Appendix A. Supplementary material Supplementary data to this article can be found online at https:// doi.org/10.1016/j.envint.2019.105391. References JAMA patient page, 2002. Low birth weight. JAMA 287, 270. Aakre, I., Henjum, S., Folven Gjengedal, E. L., Risa Haugstad, C., Vollset, M., Moubarak, K., Saleh Ahmed, T., Alexander, J., Kjellevold, M., and Molin, M. (2018). Trace Element Concentrations in Drinking Water and Urine among Saharawi Women and Young Children. Toxics 6. Ahmad, S.A., Sayed, M.H., Barua, S., Khan, M.H., Faruquee, M.H., Jalil, A., Hadi, S.A., Talukder, H.K., 2001. Arsenic in drinking water and pregnancy outcomes. Environ. Health Perspect. 109, 629–631. Asghari, M.H., Saeidnia, S., Rezvanfar, M.A., Abdollahi, M., 2015. A systematic review of the molecular mechanisms of uranium -induced reproductive toxicity. Inflamm. Allergy Drug Targets 14, 67–76. Bloom, M.S., Buck Louis, G.M., Sundaram, R., Maisog, J.M., Steuerwald, A.J., Parsons, P.J., 2015. Birth outcomes and background exposures to select elements, the Longitudinal Investigation of Fertility and the Environment (LIFE). Environ. Res. 138, 118–129. Boumans, P.W.J.M., Ivaldi, J., Slavin, W., 1991. Measuring detection limits in inductively coupled plasma emission spectrometry using the “SBR—RSDB approach”—I. A tutorial discussion of the theory. Spectrochim. Acta Part B 46, 431–445. Callan, A.C., Hinwood, A.L., Ramalingam, M., Boyce, M., Heyworth, J., McCafferty, P., Odland, J.O., 2013. Maternal exposure to metals–concentrations and predictors of
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