Associations between metal concentrations in whole blood and placenta previa and placenta accreta: the Japan Environment and Children’s Study (JECS)

Environmental Health and Preventive Medicine, Jun 2019

Placenta previa and placenta accreta associate with high morbidity and mortality for both mothers and fetus. Metal exposure may have relationships with placenta previa and placenta accreta. This study analyzed the associations between maternal metal (cadmium [Cd], lead [Pb], mercury [Hg], selenium [Se], and manganese [Mn]) concentrations and placenta previa and placenta accreta. We recruited 17,414 women with singleton pregnancies. Data from a self-administered questionnaire regarding the first trimester and medical records after delivery were analyzed. Maternal blood samples were collected to measure metal concentrations. The subjects were classified into four quartiles (Q1, Q2, Q3, and Q4) according to metal concentrations. The odds ratio for placenta previa was significantly higher among subjects with Q4 Cd than those with Q1 Cd. The odds ratio for placenta previa was significantly higher for subjects with Q2 Pb than those with Q1 Pb. Participants with placenta previa had higher Cd concentrations. However, this study was cross-sectional and lacked important information related to Cd concentration, such as detailed smoking habits and sources of Cd intake. In addition, the subjects in this study comprised ordinary pregnant Japanese women, and it was impossible to observe the relationship between a wide range of Cd exposure and placenta previa. Therefore, epidemiological and experimental studies are warranted to verify the relationship between Cd exposure and pregnancy abnormalities.

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Associations between metal concentrations in whole blood and placenta previa and placenta accreta: the Japan Environment and Children’s Study (JECS)

Research article Open Access Associations between metal concentrations in whole blood and placenta previa and placenta accreta: the Japan Environment and Children’s Study (JECS) Mayumi Tsuji1Email author, Eiji Shibata2, David J. Askew2, Seiichi Morokuma3, Yukiyo Aiko2, Ayako Senju4, 5, Shunsuke Araki5, Masafumi Sanefuji3, Yasuhiro Ishihara6, Rie Tanaka1, Koichi Kusuhara4, 5, Toshihiro Kawamoto1 and Japan Environment and Children’s Study Group Environmental Health and Preventive Medicine201924:40 https://doi.org/10.1186/s12199-019-0795-7 ©  The Author(s). 2019 Received: 3 September 2018Accepted: 23 May 2019Published: 7 June 2019 Abstract Background Placenta previa and placenta accreta associate with high morbidity and mortality for both mothers and fetus. Metal exposure may have relationships with placenta previa and placenta accreta. This study analyzed the associations between maternal metal (cadmium [Cd], lead [Pb], mercury [Hg], selenium [Se], and manganese [Mn]) concentrations and placenta previa and placenta accreta. Methods We recruited 17,414 women with singleton pregnancies. Data from a self-administered questionnaire regarding the first trimester and medical records after delivery were analyzed. Maternal blood samples were collected to measure metal concentrations. The subjects were classified into four quartiles (Q1, Q2, Q3, and Q4) according to metal concentrations. Results The odds ratio for placenta previa was significantly higher among subjects with Q4 Cd than those with Q1 Cd. The odds ratio for placenta previa was significantly higher for subjects with Q2 Pb than those with Q1 Pb. Conclusion Participants with placenta previa had higher Cd concentrations. However, this study was cross-sectional and lacked important information related to Cd concentration, such as detailed smoking habits and sources of Cd intake. In addition, the subjects in this study comprised ordinary pregnant Japanese women, and it was impossible to observe the relationship between a wide range of Cd exposure and placenta previa. Therefore, epidemiological and experimental studies are warranted to verify the relationship between Cd exposure and pregnancy abnormalities. Keywords Metal concentrationPlacenta previaPlacenta accretaPregnancy Introduction Placenta previa is a condition in which the placenta is attached to the lower uterine segment and completely or partially covers the internal cervix [1]. When chorionic villi abnormally invade the myometrium, placenta accreta occurs [2]. Currently, reported rates of placenta previa are between 0.3 and 0.8% [3, 4]. The placenta accreta rate varies because of differences in subjects; however, it is 0.4% in Japan [5, 6]. Placenta previa and placenta accreta are related: 9.3% of women with placenta previa have placenta accreta [2]. Both cases present risks to the mother and fetus. For the mother, affected pregnancies are associated with excessive hemorrhaging, damage to surrounding organs, and death. The fetus may experience preterm delivery, may be small for gestational age, or may have congenital defects [7, 8]. Successful implantation requires the following complex mechanisms: the fertilized egg/blastocyst migrates from the oviduct to the uterine cavity and orients in appropriate regions of the uterus (migration); the trophoblast attaches to the uterine epithelium (attachment); the trophoblast attaches firmly to the uterine epithelium (adhesion); the trophoblast penetrates the uterine epithelium (penetration); and the trophoblast invades the uterine endometrium (invasion) [9–11]. Placenta previa and placenta accreta share overlapping risk factors, many of which are associated with disruption of the normal uterine endometrium. These risks include previous cesarean deliveries, manual removal of the placenta, or other gynecological surgeries that result in scarring and are likely to lead to inappropriate attachment during implantation [12, 13]. Environmental exposure to smoking and air pollution has also been reported as a risk factor for placenta previa and placenta accreta [14, 15]. Smoking influences the maternal immune response and inflammatory response during pregnancy [16, 17]. Inflammation leads to female genital tract damage, including damage to the endometrial and myometrial epithelium [18]. Therefore, smoking may induce inappropriate attachment and lead to placenta previa and placenta accreta. Another important factor during the implantation process is angiogenesis [19, 20]. Placental vascularization has been found to be significantly decreased in smoke-exposed placentas [21]. Cigarettes contain many harmful substances, including heavy metals [22], and current and former smoking has been related to high cadmium (Cd) and lead (Pb) levels in uterus tissues [23]. Exposure to heavy metals, especially Cd and Pb, impacts the female reproductive system [24]. Furthermore, Cd, Pb, and mercury (Hg) might affect endometrial angiogenesis [25, 26]. However, no studies have examined the relationship between metal exposure and placenta previa and placenta accrete directly. Selenium (Se) and manganese (Mn) are essential elements which have been related to blastocyst quality and implantation [27–29]. However, there is no research to investigate the relationship between these metals and placenta previa and placenta accrete. Therefore, the purpose of this study was to examine the relationship between metal exposure and placental previa and placenta accreta using the Japan Environment and Children’s Study (JECS), which is a large cohort study. Methods Study subjects During this study, our target subjects were pregnant women participating in the JECS. They were recruited during early pregnancy at obstetric facilities and/or local government offices [30] in 15 regions across a wide geographical area in Japan between January 2011 and March 2014. Of the 17,998 women whose metal concentrations were measured, 17,414 had singleton pregnancies. After excluding women with missing data (N = 1395), 16,019 women were selected for analysis (Fig. 1). Fig. 1 Flow chart of the study subjects. Of the samples collected from the 97,979 women during mid to late pregnancy, 20,000 whole blood samples were randomly selected. To measure metal concentrations, 17,998 blood samples of women who met the QC criteria were used. Of these 17,998, 17,414 who delivered singleton pregnancies were selected. After excluding women with missing data (N = 1395), the final study population comprised of 16,019 women. Cd, cadmium; Pb, lead; Hg, mercury; Se, selenium; Mn, manganese; QC, quality control Questionnaires Self-administered questionnaires were provided at prenatal examinations or by mail to the women twice during pregnancy (during the first trimester [T1] and the second/third trimester [T2]). Data from the questionnaire provided during T1 were used in this study. Medical record transcription was performed by physicians, midwives/nurses, or research coordinators after delivery [30–32]. Data for those with and without placenta previa and placenta accreta were obtained from medical records. The present study was based on the jecs-ag-ai-20,160,424 data set, which was released in June 2016 and revised in October 2016. Blood collection Metal concentrations were measured in T2 blood samples comprising 33 mL of blood collected from each pregnant mother. The present study was based on the jecs-mtl-ai-20,170,403 data set, which was released in April 2017. Measurements of metal concentrations in blood We measured the metal concentrations in the blood according to our previous report [33]. Briefly, blood samples with sodium ethylenediaminetetraacetic acid (EDTA) were transferred to a central laboratory and stored at − 80 °C before use. A standard solution comprising all target elements except Hg was prepared in 0.14 M nitric acid. An Hg standard solution was produced using a solution made from 0.056 M nitric acid, 0.5% w/v EDTA, and 1% v/v tetramethylammonium hydroxide (TMAH). The final concentrations of Hg, Pb, Cd, Mn, and Se in the standard solution were 200, 200, 20, 600, and 2000 ng/g, respectively. An internal standard (yttrium, indium, and thallium at 250 ng/g) was prepared using 0.14 M nitric acid. Blood samples (200 μL) were diluted (1:19) with the dilution solution (2% v/v butan-1-ol, 0.1% TMAH, 0.05% w/v polyoxyethlene octylphenyl ether, and 0.05% w/v H4EDTA) [10] and vortex-mixed before the inductively coupled plasma mass spectrometry (ICP-MS) analysis. ICP-MS measurements of metals in the blood were performed using Agilent 7700 ICP-MS (Agilent Technologies, Tokyo, Japan). Method detection limits for each analyte were calculated according to the method described previously [34]. The intensity of Pb isotypes was the summation of that of 206Pb, 207Pb, and 208Pb. To correct the spectral overlap from molybdenum oxide (95Mo16O), the intensity of 111Cd was calculated using the following equation: $$ \left[\mathrm{Cd}\right]=\left[m/z\ 111\ \mathrm{intensity}\right]-\left[m/z\ 95\ \mathrm{intensity}\right]\times \left[95\mathrm{Mo}16\mathrm{O}\ \mathrm{generation}\ \mathrm{rate}\right] $$ The 95Mo16O generation rate was derived from the following equation: $$ \left[95\mathrm{Mo}16\mathrm{O}\ \mathrm{generation}\ \mathrm{rate}\right]=\left[\mathrm{the}\ \mathrm{intensity}\ \mathrm{of}\ m/z\ 111\ \mathrm{when}\ 100\;\mathrm{ppb}\ 95\mathrm{Mo}\ \mathrm{standard}\ \mathrm{solution}\ \mathrm{was}\ \mathrm{analyzed}\right]/\left[\mathrm{the}\ \mathrm{intensity}\ \mathrm{of}\ m/z\ 96\ \mathrm{when}\ 100\;\mathrm{ppb}\ 95\mathrm{Mo}\ \mathrm{standard}\ \mathrm{solution}\ \mathrm{was}\ \mathrm{analyzed}\right] $$ Statistical methods Two-group comparisons were performed using the Mann-Whitney U test and multivariable logistic regression analyses. The p values of the multivariable logistic regression analysis were calculated after adjusting for age, smoking, smoking habits of the partner, drinking habits, gravidity, parity, number of cesarean deliveries, and geographic region [35, 36]. Placenta previa was added as a covariate when comparisons were performed with or without placenta accreta. Subjects were divided equally into quartiles depending on individual metal concentrations (first quartile [Q1], second quartile [Q2], third quartile [Q3], fourth quartile [Q4]); these quartiles were used in the multivariable logistic regression analysis and trend test. All analyses were performed using Stata version 14 (Stata Corp., College Station, TX, USA), and statistical significance was assumed when p < 0.05 (two-sided). Results Table 1 shows characteristics of the study population. The rates of placenta previa and placenta accreta were 0.5% and 0.2%, respectively, among subjects. Four women had placenta previa and placenta accreta. Table 1 Study population characteristics   Total (N = 16,019) Previa Accreta Without (N = 15,929) With (N = 90) p value† Without (N = 15,980) With (N = 39) P value† Age (years) 31.3 ± 5.0 31.3 ± 5.0 32.9 ± 4.7 0.003 31.3 ± 5.0 34.1 ± 5.2 0.002 Smoking habits  Never 9194 (57) 9136 (57) 58 (64)   9173 (57) 21 (54)    Former 6002 (37) 5974 (38) 28 (31) 0.224 5989 (37) 13 (33) 1.000  Current 823 (5) 819 (5) 4 (4) 0.817 818 (5) 5 (13) 0.057 Smoking habits of partner  Never 4281 (27) 4251 (27) 30 (33)   4265 (27) 16 (41)    Former 4339 (27) 4314 (27) 25 (28) 0.501 4326 (27) 13 (33) 0.582  Current 7399 (46) 7364 (46) 35 (39) 0.122 7389 (46) 10 (26) 0.013 Drinking habits  No 14,386 (90) 14,307 (90) 79 (88)   14,355 (90) 31 (79)    Yes 1633 (10) 1622 (10) 11 (12) 0.485 1625 (10) 8 (21) 0.055 Gravidity  Primigravida 4758 (30) 4733 (30) 25 (28)   4751 (30) 7 (18)    Multigravida 11,261 (70) 11,196 (70) 65 (72) 0.730 11,229 (70) 32 (82) 0.117 Parity  Nulliparous 6385 (40) 6348 (40) 37 (41)   6372 (40) 13 (33)    Multiparous 9634 (60) 9581 (60) 53 (59) 0.829 9608 (60) 26 (67) 0.513 Number of cesarean deliveries  0 14,576 (91) 14,496 (91) 80 (89)   14,542 (91) 34 (87)    1 1111 (7) 1106 (7) 5 (6) 0.833 1108 (7) 3 (8) 0.744  2 305 (2) 300 (2) 5 (6) 0.030 303 (2) 2 (5) 0.168   ≥ 3 27 (0) 27 (0) 0 (0) 1.000 27 (0) 0 (0) 1.000 Values are mean ± SD or number (%) †p values for age were obtained using Welch’s t test. p values for other factors were obtained using Fisher’s exact test Table 2 shows the distribution of metal concentrations by smoking habits. Cd and Pb concentrations of current smokers were high in our study (Cd; p < 0.001, Pb; p < 0.001 by analysis of variance [ANOVA]). In contrast, Hg and Mn concentrations of current smokers were low in our study (Hg; p < 0.001, Mn; p < 0.001 by ANOVA). Table 2 The distribution of metal concentrations by smoking habits   Median (ng/g) (25th and 75th percentiles)a p value* Total (N = 16,019) Smoking habits Never (N = 9194) Former (N = 6002) Current (N = 823) Cd 0.66 (0.50, 0.91) 0.64 (0.48, 0.86) 0.66 (0.50, 0.90) 1.07 (0.78, 1.44) < 0.001 Pb 5.96 (4.80, 7.45) 5.81 (4.69, 7.24) 6.08 (4.93, 7.61) 6.92 (5.56, 8.74) < 0.001 Hg 3.65 (2.57, 5.16) 3.75 (2.65, 5.27) 3.53 (2.51, 5.00) 3.40 (2.35, 5.02) < 0.001 Se 169 (158, 183) 169 (157, 183) 170 (158, 183) 170 (158, 184) 0.339 Mn 15.3 (12.6, 18.7) 15.5 (12.8, 18.8) 15.2 (12.5, 18.6) 14.8 (12.3, 17.9) < 0.001 *p values were obtained using ANOVA aNatural log-transformed variables were used for ANOVA Figure 2 shows the relationship between metal concentrations and placenta previa. There was a significant difference in Cd concentrations for the two placenta previa groups (median [ng/g]: without, 0.66; with, 0.79; P = 0.004). There were no significant differences between other metals and placenta previa. Fig. 2 Relationships between metal concentrations in the blood and placenta previa. The relationships between metal concentrations in the second/third trimester (T2) blood and placenta previa are shown. A box plot displays a box bordered at the 25th and 75th percentiles of the variable on the y-axis with a median line at the 50th percentile of each metal concentration. p values were calculated using the Mann-Whitney U test. a Relationship between Cd concentration and placenta previa. b Relationship between Pb concentration and placenta previa. c Relationship between Hg concentration and placenta previa. d Relationship between Se concentration and placenta previa. e Relationship between Mn concentration and placenta previa. Cd, cadmium; Pb, lead; Hg, mercury; Se, selenium; Mn, manganese Figure 3 shows the relationship between metal concentrations and placenta accreta. There were no significant differences between all metals and placenta accreta. Fig. 3 Relationships between metal concentrations in the blood and placenta accreta. The relationships between metal concentrations in the second/third trimester (T2) blood and placenta accreta are shown. A box plot displays a box bordered at the 25th and 75th percentiles of the variable on the y-axis with a median line at the 50th percentile of each metal concentration. p values were calculated using the Mann-Whitney U test. a Relationship between Cd concentration and placenta accreta. b Relationship between Pb concentration and placenta accreta. c Relationship between Hg concentration and placenta accreta. d Relationship between Se concentration and placenta accreta. e Relationship between Mn concentration and placenta accreta. Cd, cadmium; Pb, lead; Hg, mercury; Se, selenium; Mn, manganese To further assess the association between levels of metal concentrations and placenta previa and placenta accreta, we performed multivariable logistic regression analyses by using the quartile variables of metal concentrations. The odds ratio (OR) for placenta previa was significantly higher among subjects with Q4 Cd than those with Q1 Cd (OR, 2.06; 95% confidence interval [CI], 1.07, 3.98; p = 0.031). Further, the OR for placenta previa was significantly higher among subjects with Q2 Pb than those with Q1 Pb (OR, 2.59; 95% CI, 1.40, 4.80; p = 0.003). There was a significant relationship between placenta previa and Pb concentrations (P for trend = 0.007). There was no significant relationship between placenta accreta and metal concentrations (Table 3). Table 3 Results of multivariable analysis regarding the relationship between quartile concentrations of metals, placenta previa, and placenta accreta Quartile concentration of metals (ng/g) Previa Accreta Without (N = 15,929) With (N = 90) OR (95% CI) p value* Without (N = 15,980) With (N = 39) OR (95% CI) p value ** Cd  Q1 (≤ 0.496) 3967 14 1.00 (referent)   3971 10 1.00 (referent)    Q2 (0.497–0.661) 3999 20 1.37 (0.69–2.72) 0.375 4012 7 0.55 (0.21–1.46) 0.234  Q3 (0.662–0.904) 3982 25 1.67 (0.86–3.26) 0.129 3993 14 1.01 (0.44–2.33) 0.981  Q4 (≥ 0.905) 3981 31 2.06 (1.07–3.98) 0.031 4004 8 0.46 (0.17–1.22) 0.120     P for trend = 0.146    P for trend = 0.205 Pb  Q1 (≤4.79) 3969 14 1.00 (referent)   3976 7 1.00 (referent)    Q2 (4.80–5.95) 3987 37 2.59 (1.40–4.80) 0.003 4012 12 1.46 (0.57–3.76) 0.429  Q3 (5.96–7.44) 3975 19 1.32 (0.66–2.64) 0.436 3981 13 1.68 (0.66–4.24) 0.276  Q4 (≥ 7.45) 3998 20 1.34 (0.67–2.67) 0.411 4011 7 0.79 (0.27–2.30) 0.667     P for trend = 0.007    P for trend = 0.345 Hg  Q1 (≤ 2.56) 3948 20 1.00 (referent)   3959 9 1.00 (referent)    Q2 (2.57–3.64) 3987 29 1.37 (0.78–2.44) 0.276 4003 13 1.31 (0.55–3.08) 0.540  Q3 (3.65–5.15) 4004 19 0.89 (0.47–1.67) 0.708 4012 11 1.18 (0.48–2.86) 0.721  Q4 (≥ 5.16) 3990 22 1.03 (0.56–1.90) 0.924 4006 6 0.63 (0.22–1.77) 0.378     P for trend = 0.477    P for trend = 0.458 Se  Q1 (≤ 157) 3961 27 1.00 (referent)   3978 10 1.00 (referent)    Q2 (158–168) 3687 21 0.84 (0.47–1.49) 0.544 3700 8 0.86 (0.34–2.20) 0.756  Q3 (169–182) 4197 21 0.73 (0.41–1.30) 0.284 4209 9 0.83 (0.34–2.07) 0.695  Q4 (≥ 183) 4084 21 0.75 (0.42–1.33) 0.320 4093 12 1.13 (0.48–2.63) 0.784     P for trend = 0.693    P for trend = 0.901 Mn  Q1 (≤ 12.5) 3858 21 1.00 (referent)   3871 8 1.00 (referent)    Q2 (12.6–15.2) 3961 22 1.05 (0.58–1.91) 0.877 3966 17 2.11 (0.91–4.92) 0.083  Q3 (15.3–18.6) 4100 23 1.06 (0.58–1.92) 0.853 4116 7 0.82 (0.31–2.29) 0.710  Q4 (≥ 18.7) 4010 24 1.14 (0.63–2.06) 0.656 4027 7 0.85 (0.31–2.37) 0.758     P for trend = 0.977    P for trend = 0.080 *p values were obtained from the multivariable logistic regression analysis adjusted for age, smoking, smoking habits of the partner, drinking habits, gravidity, parity, number of cesarean deliveries, and geographic region **p values were obtained from the multivariable logistic regression analysis adjusted for age, smoking, smoking habits of the partner, drinking habits, gravidity, parity, number of cesarean deliveries, placenta previa, and geographic region Discussion Two significant results were obtained during this research. First, the group with placenta previa had higher Cd concentrations than the group without placenta previa. In addition, subjects with Q4 Cd were at higher OR for placenta previa than those with Q1 Cd. Second, subjects with Q2 Pb were at significantly higher OR for placenta previa than those with Q1 Pb. Cd and Pb have several exposure sources, such as food and soil [37, 38]. Especially smoking is a major source of Cd and Pb [39]. Other reports have described the relationship between smoking and placenta previa [14, 40]. Indeed, the Cd and Pb concentrations of smokers were high in our study. Therefore, tobacco acts as one of the definite sources of Cd and Pb exposure. However, we categorized the smoking habits for the two groups—never smokers or former/current smokers—and we performed multivariable logistic regression analyses between metal concentrations and placenta previa. In the group of never smokers, the OR of placenta previa was higher among subjects with Q2–Q4 Cd and Pb than those with Q1 (Additional file 1: Table S1). These results show the same trend as seen in Table 3, which involved analysis without dividing the groups into never smokers and former/current smokers. Therefore, the possibility that Cd and Pb are themselves related to placenta previa cannot be discounted. The median Cd concentration in our study was 0.66 ng/g, which was lower than those reported previously in Japan [41, 42] and low compared to those of residents living in Cd-polluted areas [43]. Regarding Cd, in recent years, it has been reported that exposure to low-dose Cd affects the health of those in non-polluted areas and non-smokers [44]. Therefore, further epidemiological studies and experimental studies involving cell lines and animals are warranted to clarify the relationship between placenta previa and various dose Cd exposure. The OR for placenta previa was significantly higher among subjects with Q2 Pb than those with Q1 Pb. Women with Q3 Pb group and Q4 Pb group did not demonstrate a significant relationship; however, the OR for placenta previa was higher in those in the Q1 Pb group. It is not clear why Q2 Pb had the highest OR. Therefore, although not in a dose-dependent manner, it cannot be denied that Pb exposure may have some effect on the placenta previa. Our study has several limitations. First, the source of exposure to Cd in this study was unknown. Smoking is one of the sources of exposure to Cd; however, we had no information regarding the number of cigarettes per day or when subjects quit smoking. Therefore, we could not accurately determine the influence of Cd exposure attributable to smoking. In addition to smoking, there are various other sources of Cd. Among all food sources, rice was the most significant contributor of Cd, followed by vegetables, seaweed, seafood, and millet [45]. Therefore, Cd is absorbed into the human body via these foods. The food intake of some individuals in Japan is regionally dependent. For example, residents in the area along the sea coast have a tendency to eat more seafood, such as shellfish, squid, and crab, which contain much Cd [46, 47]. Therefore, it is necessary to investigate the relationships between the source of Cd exposure, intake amount, blood concentrations, and placenta previa, and to consider the regional characteristics of the food consumed. Second, this study only investigated the relationship between placenta previa and low-dose Cd exposure. We could not clarify which dose of Cd (low or high) had the most influence on placenta previa. Therefore, in the future, it will be important to compare high Cd-polluted areas and low-Cd-polluted areas and high Cd intake groups and low-Cd intake groups. Additional experiments are needed to uncover direct relationships between Cd and placenta previa and/or the mechanism by which Cd can affect placental formation and development. Third, metal concentrations in the placental tissue were not measured in the JECS study. In the future, studies should aim to measure the concentrations of the metal in the placental tissue and to investigate the relationship between these concentrations and placental abnormalities. These studies should help clarify the relationship between metal exposure and placental abnormalities. Fourth, this study was a cross-sectional study using JECS data. Therefore, the causal relationship between Cd exposure and placenta previa could not be considered using only this study. Iron deficiency during pregnancy leads to increased Cd absorption and burden on the body [48]. However, it is unknown whether the increase in Cd absorption caused by iron deficiency affects the onset of placenta previa. To clarify the causal relationship between iron deficiency, Cd absorption, and placenta previa, it is necessary to measure Cd, iron, and ferritin concentrations in the blood throughout pregnancy, especially during the first trimester, which is an important time for normal implantation and placentation [3]. Dietary habits and nutritional status during pregnancy may be related to pregnancy abnormalities [49, 50]; therefore, it is also important to monitor the diet during pregnancy. Furthermore, the JECS study was a cohort study; therefore, it is important to link the relationship between maternal metal exposure, pregnancy abnormalities, and children’s health in the future. Conclusion The group with placenta previa had higher whole blood concentrations of Cd than did the group without placenta previa. However, this study was cross-sectional and did not aim at Cd exposure and its health effects specifically, resulting in a lack of important information regarding Cd concentration, such as detailed smoking habits and sources of Cd intake. In addition, this study was conducted on ordinary Japanese pregnant women, and it was impossible to observe the relationship between a wide range of Cd exposure and placenta previa. Placenta previa involves the risk of excessive hemorrhaging, damage to surrounding organs, and death for the mother. In addition, it can cause preterm birth, small for the gestational age status for the fetus, and congenital defects in the fetus. To prevent placenta previa, maintain the mother’s health, and protect the health of the fetus, epidemiological and experimental studies are warranted to verify the relationship between Cd exposure and pregnancy abnormalities. Abbreviations Cd:  Cadmium CI:  Confidence interval EDTA:  Ethylenediaminetetraacetic acid Hg:  Mercury ICP-MS:  Inductively coupled plasma mass spectrometry Mn:  Manganese OR:  Odds ratio Pb:  Lead Q1:  First quartile Q2:  Second quartile Q3:  Third quartile Q4:  Fourth quartile QC:  Quality control Se:  Selenium T1:  The first trimester T2:  The second/third trimester TMAH:  Tetramethylammonium hydroxide Declarations Acknowledgements Members of the Japan Environment and Children’s Study (JECS) as of 2017 (principal investigator, Toshihiro Kawamoto): Hirohisa Saito (National Center for Child Health and Development, Tokyo, Japan), Reiko Kishi (Hokkaido University, Sapporo, Japan), Nobuo Yaegashi (Tohoku University, Sendai, Japan), Koichi Hashimoto (Fukushima Medical University, Fukushima, Japan), Chisato Mori (Chiba University, Chiba, Japan), Shuichi Ito (Yokohama City University, Yokohama, Japan), Zentaro Yamagata (University of Yamanashi, Chuo, Japan), Hidekuni Inadera (University of Toyama, Toyama, Japan), Michihiro Kamijima (Nagoya City University, Nagoya, Japan), Takeo Nakayama (Kyoto University, Kyoto, Japan), Hiroyasu Iso (Osaka University, Suita, Japan), Masayuki Shima (Hyogo College of Medicine, Nishinomiya, Japan), Yasuaki Hirooka (Tottori University, Yonago, Japan), Narufumi Suganuma (Kochi University, Nankoku, Japan), Koichi Kusuhara (University of Occupational and Environmental Health, Kitakyushu, Japan), and Takahiko Katoh (Kumamoto University, Kumamoto, Japan). The Japan Environment and Children’s Study was funded by the Ministry of the Environment, Japan. The findings and conclusions of this study are the sole responsibility of the authors and do not represent the official views of the Japanese government. We thank Editage (https://www.editage.jp) for English language editing. Funding This study was funded and supported by the Ministry of the Environment of Japan. The findings and conclusions of this article are solely the responsibility of the authors and do not represent the official views of this government agency. Authors’ contributions MT, DA, SM, MS, TK, and ES contributed to the conception of the study. MT, DA, AS, SA, YI, RT, KK, TK, and ES performed the statistical analyses and wrote the manuscript. MT, SM, YA, KK, and ES contributed to the experimental design and recruitment. All authors have read and approved the final manuscript. Ethics approval and consent to participate The JECS was approved by the Institutional Review Board of the Japan National Institute for Environmental Studies (approval number: 2017-002), and the Ethics Committees of all participating institutions. The study was conducted in accordance with the Declaration of Helsinki and other national regulations. Written informed consent was obtained from all study participants. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Additional files Additional file 1: Table S1. Results of multivariable analysis for determining the relationship between quartile concentrations of metals and placenta previa in never smokers and former/current smokers. (DOCX 26 kb) Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Authors’ Affiliations (1) Department of Environmental Health, University of Occupational and Environmental Health, Kitakyushu, Japan (2) Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan (3) Research Center for Environmental and Developmental Medical Sciences, Kyushu University, Fukuoka, Japan (4) Japan Environment and Children’s Study, University of Occupational and Environmental Health Subunit Center, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan (5) Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan (6) Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima, Japan References Lee HJ, Lee YJ, Ahn EH, Kim HC, Jung SH, Chang SW, et al. 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Mayumi Tsuji, Eiji Shibata, David J. Askew, Seiichi Morokuma, Yukiyo Aiko, Ayako Senju, Shunsuke Araki, Masafumi Sanefuji, Yasuhiro Ishihara, Rie Tanaka, Koichi Kusuhara, Toshihiro Kawamoto. Associations between metal concentrations in whole blood and placenta previa and placenta accreta: the Japan Environment and Children’s Study (JECS), Environmental Health and Preventive Medicine, 2019, 40, DOI: 10.1186/s12199-019-0795-7