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Jung-Wei Chang, Ching‐Chang Lee, W. Pan, W. Chou, Han-Bin Huang, H. Chiang, P. Huang (2017)
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Why was the Taiwan Maternal and Infant Cohort Study (TMICS) established? This cohort was established in response to a food contamination scandal that became news in Taiwan in 2011. In that scandal, endocrine-disrupting phthalates, especially di-(2-ethylhexyl) phthalate (DEHP), were deliberately added to a variety of foods commonly consumed by children there.1 Although the food scandal wound down, environmental exposure to phthalates remains ubiquitous in daily life in Taiwan.2–4 Vulnerable populations such as pregnant women and children can be exposed to these products through different routes, including food ingestion, inhalation and dermal absorption in their daily life.3,5–7 Considering the potential dangers, epidemiologists from northern, central, southern and eastern Taiwan cooperated in establishing this nationwide prospective birth cohort, known as Taiwan Maternal and Infant Cohort Study (TMICS), to study environmental phthalate exposure and the health status of mothers and children in Taiwan. The primary objectives of the TMICS study are: (i) to measure the exposure levels of the common environmental hazardous substances, particularly phthalates, in susceptible populations, including pregnant women and their children; (ii) to examine the effect of maternal exposure to common environmental hazards, particularly phthalates, in Taiwan on a variety of health outcomes in their offspring; (iii) to study the gene-environment interaction; and (iv) to establish a repository of biospecimens for future environmental and health studies. For example, TMICS also plans to analyse the markers of exposure to other potentially hazardous substances in the environment, in order to address a wider range of environment and health concerns. Who is in the cohort? For this multicentre hospital-based birth cohort study, we started in October 2012 to recruit pregnant women who came into nine hospitals (Figure 1a), three in northern Taiwan, three in central Taiwan, two in southern and one in eastern Taiwan, for routine antenatal examinations their third trimester (Weeks 29 to 40). They were enrolled if they were willing to participate in this study. In addition, we also used the enrollees’ previous data if they had been visiting since their first or second trimester (18 weeks and onward). This study was approved by the ethics committees from National Health Research Institutes (NHRI) and the nine hospitals. We excluded those who had histories of systematic diseases such as cancer, hypertension and diabetes or chronic use of corticosteroids or immunosuppressant drugs, those who were more than 45 years old and those who had multiparous pregnancies. As of May 2015, overall 2136 participants participated in this cohort study7 and 1676 women had answered our questionnaires. Of these women, 1638 provided one-spot urine samples during their third trimester for the analysis of 11 phthalate metabolites. After excluding subjects with no urinary creatinine data (N = 7), we were left with the data of 1631 subjects for analyses (Figure 1b). Figure 1 View largeDownload slide Study map (a) and study flow chart (b). Figure 1 View largeDownload slide Study map (a) and study flow chart (b). The mean age [±standard deviation SD)] of 1631 subjects was 31.38 (±4.56) years. About 42.2% of the participant mothers were experiencing their first pregnancy, and most of the participants had college education (81.9%). Less than 6% of them had smoking and drinking habits during pregnancy. The male/female ratio of their newborns was approximately 1: 1. The newborn ages were 38.56 ± 1.27 weeks, with an average height and weight of 49.41 ± 2.25 cm and 3107.71 ± 393.99 g, respectively (Table 1). Table 1. Demographic characteristics of participant mothers and their newborns (n = 1631) Variables Northern Taiwan Middle Taiwan Southern Taiwan East Taiwan Total N 279 617 394 341 1631 Mean ± SD or n (%) Mother Age (years) 32.55 ± 3.77 31.82 ± 4.28 30.68 ± 4.83 30.88 ± 4.85 31.38 ± 4.56 Education level <college 8 (3.92) 64 (12.43) 114 (33.00) 64 (20.30) 250 (18.12) ≥college 196 (96.08) 451 (87.57) 231 (67.00) 252 (79.70) 1130 (81.88) Parity First 103 (47.69) 176 (36.36) 153 (40.91) 154 (49.04) 586 (42.22) Cigarette smoking Yes 8 (3.94) 20 (3.89) 17 (5.00) 20 (6.33) 65 (4.73) Drinking alcohol Yes 11 (5.42) 26 (5.06) 14 (4.10) 23 (7.28) 74 (5.39) Gestational diabetes mellitus Yes 9 (4.46) 26 (5.41) 22 (5.91) 7 (2.30) 64 (4.71) Gestational hypertension Yes 2 (0.99) 2 (0.41) 3 (0.80) 3 (0.99) 10 (0.73) Uses plastic bag for food (two times/week) Yes 146 (83.43) 328 (77.00) 178 (54.60) 133 (66.83) 785 (69.72) Uses plastic cup for hot water (two times/week) Yes 49 (28.00) 127 (29.81) 65 (20.00) 56 (28.28) 297 (26.42) Washes hands before eating Yes 70 (40.23) 164 (38.86) 164 (50.31) 107 (54.31) 505 (45.13) Takes vitaminit B complex Yes 29 (17.90) 93 (20.90) 46 (21.60) 39 (12.70) 207 (18.37) Takes folic acid Yes 66 (38.37) 215 (45.94) 79 (33.76) 98 (31.61) 458 (38.68) Uses shower gel Yes 170 (86.73) 453 (88.82) 181 (93.30) 274 (87.54) 1078 (88.87) Newborn Sex Male 111 (49.55) 255 (52.04) 198 (51.97) 165 (52.72) 729 (51.78) Female 113 (50.45) 235 (47.96) 183 (48.03) 148 (47.28) 679 (48.22) Gestational age (weeks) 38.56 ± 1.37 38.59 ± 1.34 38.57 ± 1.20 38.53 ± 1.17 38.56 ± 1.27 Body weight (g) 3106.75 ± 362.40 3111.23 ± 428.31 3088.64 ± 372.75 3125.79 ± 385.61 3107.71 ± 393.99 Body length(cm) 48.73 ± 2.16 49.55 ± 2.47 49.76 ± 2.34 49.24 ± 1.66 49.41 ± 2.25 Head circumference (cm) 34.08 ± 1.69 33.89 ± 1.31 33.06 ± 1.34 33.74 ± 1.23 33.65 ± 1.39 Chest circumference (cm) 32.37 ± 2.00 32.01 ± 1.66 32.33 ± 1.67 33.04 ± 1.52 32.39 ± 1.71 Variables Northern Taiwan Middle Taiwan Southern Taiwan East Taiwan Total N 279 617 394 341 1631 Mean ± SD or n (%) Mother Age (years) 32.55 ± 3.77 31.82 ± 4.28 30.68 ± 4.83 30.88 ± 4.85 31.38 ± 4.56 Education level <college 8 (3.92) 64 (12.43) 114 (33.00) 64 (20.30) 250 (18.12) ≥college 196 (96.08) 451 (87.57) 231 (67.00) 252 (79.70) 1130 (81.88) Parity First 103 (47.69) 176 (36.36) 153 (40.91) 154 (49.04) 586 (42.22) Cigarette smoking Yes 8 (3.94) 20 (3.89) 17 (5.00) 20 (6.33) 65 (4.73) Drinking alcohol Yes 11 (5.42) 26 (5.06) 14 (4.10) 23 (7.28) 74 (5.39) Gestational diabetes mellitus Yes 9 (4.46) 26 (5.41) 22 (5.91) 7 (2.30) 64 (4.71) Gestational hypertension Yes 2 (0.99) 2 (0.41) 3 (0.80) 3 (0.99) 10 (0.73) Uses plastic bag for food (two times/week) Yes 146 (83.43) 328 (77.00) 178 (54.60) 133 (66.83) 785 (69.72) Uses plastic cup for hot water (two times/week) Yes 49 (28.00) 127 (29.81) 65 (20.00) 56 (28.28) 297 (26.42) Washes hands before eating Yes 70 (40.23) 164 (38.86) 164 (50.31) 107 (54.31) 505 (45.13) Takes vitaminit B complex Yes 29 (17.90) 93 (20.90) 46 (21.60) 39 (12.70) 207 (18.37) Takes folic acid Yes 66 (38.37) 215 (45.94) 79 (33.76) 98 (31.61) 458 (38.68) Uses shower gel Yes 170 (86.73) 453 (88.82) 181 (93.30) 274 (87.54) 1078 (88.87) Newborn Sex Male 111 (49.55) 255 (52.04) 198 (51.97) 165 (52.72) 729 (51.78) Female 113 (50.45) 235 (47.96) 183 (48.03) 148 (47.28) 679 (48.22) Gestational age (weeks) 38.56 ± 1.37 38.59 ± 1.34 38.57 ± 1.20 38.53 ± 1.17 38.56 ± 1.27 Body weight (g) 3106.75 ± 362.40 3111.23 ± 428.31 3088.64 ± 372.75 3125.79 ± 385.61 3107.71 ± 393.99 Body length(cm) 48.73 ± 2.16 49.55 ± 2.47 49.76 ± 2.34 49.24 ± 1.66 49.41 ± 2.25 Head circumference (cm) 34.08 ± 1.69 33.89 ± 1.31 33.06 ± 1.34 33.74 ± 1.23 33.65 ± 1.39 Chest circumference (cm) 32.37 ± 2.00 32.01 ± 1.66 32.33 ± 1.67 33.04 ± 1.52 32.39 ± 1.71 Table 1. Demographic characteristics of participant mothers and their newborns (n = 1631) Variables Northern Taiwan Middle Taiwan Southern Taiwan East Taiwan Total N 279 617 394 341 1631 Mean ± SD or n (%) Mother Age (years) 32.55 ± 3.77 31.82 ± 4.28 30.68 ± 4.83 30.88 ± 4.85 31.38 ± 4.56 Education level <college 8 (3.92) 64 (12.43) 114 (33.00) 64 (20.30) 250 (18.12) ≥college 196 (96.08) 451 (87.57) 231 (67.00) 252 (79.70) 1130 (81.88) Parity First 103 (47.69) 176 (36.36) 153 (40.91) 154 (49.04) 586 (42.22) Cigarette smoking Yes 8 (3.94) 20 (3.89) 17 (5.00) 20 (6.33) 65 (4.73) Drinking alcohol Yes 11 (5.42) 26 (5.06) 14 (4.10) 23 (7.28) 74 (5.39) Gestational diabetes mellitus Yes 9 (4.46) 26 (5.41) 22 (5.91) 7 (2.30) 64 (4.71) Gestational hypertension Yes 2 (0.99) 2 (0.41) 3 (0.80) 3 (0.99) 10 (0.73) Uses plastic bag for food (two times/week) Yes 146 (83.43) 328 (77.00) 178 (54.60) 133 (66.83) 785 (69.72) Uses plastic cup for hot water (two times/week) Yes 49 (28.00) 127 (29.81) 65 (20.00) 56 (28.28) 297 (26.42) Washes hands before eating Yes 70 (40.23) 164 (38.86) 164 (50.31) 107 (54.31) 505 (45.13) Takes vitaminit B complex Yes 29 (17.90) 93 (20.90) 46 (21.60) 39 (12.70) 207 (18.37) Takes folic acid Yes 66 (38.37) 215 (45.94) 79 (33.76) 98 (31.61) 458 (38.68) Uses shower gel Yes 170 (86.73) 453 (88.82) 181 (93.30) 274 (87.54) 1078 (88.87) Newborn Sex Male 111 (49.55) 255 (52.04) 198 (51.97) 165 (52.72) 729 (51.78) Female 113 (50.45) 235 (47.96) 183 (48.03) 148 (47.28) 679 (48.22) Gestational age (weeks) 38.56 ± 1.37 38.59 ± 1.34 38.57 ± 1.20 38.53 ± 1.17 38.56 ± 1.27 Body weight (g) 3106.75 ± 362.40 3111.23 ± 428.31 3088.64 ± 372.75 3125.79 ± 385.61 3107.71 ± 393.99 Body length(cm) 48.73 ± 2.16 49.55 ± 2.47 49.76 ± 2.34 49.24 ± 1.66 49.41 ± 2.25 Head circumference (cm) 34.08 ± 1.69 33.89 ± 1.31 33.06 ± 1.34 33.74 ± 1.23 33.65 ± 1.39 Chest circumference (cm) 32.37 ± 2.00 32.01 ± 1.66 32.33 ± 1.67 33.04 ± 1.52 32.39 ± 1.71 Variables Northern Taiwan Middle Taiwan Southern Taiwan East Taiwan Total N 279 617 394 341 1631 Mean ± SD or n (%) Mother Age (years) 32.55 ± 3.77 31.82 ± 4.28 30.68 ± 4.83 30.88 ± 4.85 31.38 ± 4.56 Education level <college 8 (3.92) 64 (12.43) 114 (33.00) 64 (20.30) 250 (18.12) ≥college 196 (96.08) 451 (87.57) 231 (67.00) 252 (79.70) 1130 (81.88) Parity First 103 (47.69) 176 (36.36) 153 (40.91) 154 (49.04) 586 (42.22) Cigarette smoking Yes 8 (3.94) 20 (3.89) 17 (5.00) 20 (6.33) 65 (4.73) Drinking alcohol Yes 11 (5.42) 26 (5.06) 14 (4.10) 23 (7.28) 74 (5.39) Gestational diabetes mellitus Yes 9 (4.46) 26 (5.41) 22 (5.91) 7 (2.30) 64 (4.71) Gestational hypertension Yes 2 (0.99) 2 (0.41) 3 (0.80) 3 (0.99) 10 (0.73) Uses plastic bag for food (two times/week) Yes 146 (83.43) 328 (77.00) 178 (54.60) 133 (66.83) 785 (69.72) Uses plastic cup for hot water (two times/week) Yes 49 (28.00) 127 (29.81) 65 (20.00) 56 (28.28) 297 (26.42) Washes hands before eating Yes 70 (40.23) 164 (38.86) 164 (50.31) 107 (54.31) 505 (45.13) Takes vitaminit B complex Yes 29 (17.90) 93 (20.90) 46 (21.60) 39 (12.70) 207 (18.37) Takes folic acid Yes 66 (38.37) 215 (45.94) 79 (33.76) 98 (31.61) 458 (38.68) Uses shower gel Yes 170 (86.73) 453 (88.82) 181 (93.30) 274 (87.54) 1078 (88.87) Newborn Sex Male 111 (49.55) 255 (52.04) 198 (51.97) 165 (52.72) 729 (51.78) Female 113 (50.45) 235 (47.96) 183 (48.03) 148 (47.28) 679 (48.22) Gestational age (weeks) 38.56 ± 1.37 38.59 ± 1.34 38.57 ± 1.20 38.53 ± 1.17 38.56 ± 1.27 Body weight (g) 3106.75 ± 362.40 3111.23 ± 428.31 3088.64 ± 372.75 3125.79 ± 385.61 3107.71 ± 393.99 Body length(cm) 48.73 ± 2.16 49.55 ± 2.47 49.76 ± 2.34 49.24 ± 1.66 49.41 ± 2.25 Head circumference (cm) 34.08 ± 1.69 33.89 ± 1.31 33.06 ± 1.34 33.74 ± 1.23 33.65 ± 1.39 Chest circumference (cm) 32.37 ± 2.00 32.01 ± 1.66 32.33 ± 1.67 33.04 ± 1.52 32.39 ± 1.71 How often will they be followed up? The mothers and infants were followed up regularly, using questionnaires and collecting samples for laboratory evaluation. With regard to the administration of questionnaires, upon recruitment in their trimester, we administered a standardized questionnaire to collect personal information. At delivery and 2–3 weeks following delivery, we administered short follow-up questionnaires focusing on current maternal diet and nutrient intake as well as newborn physical parameters. From October 2016, we started following each offspring when he or she reached 3 years old. At that time, in addition to re-administering a questionnaire to the mothers collecting detailed personal information, we also administered a comprehensive questionnaire about the children, collecting physical parameters as well as detailed information about their daily life habits and activities (Table 2). Table 2. Questionnaire data, physical parameters and biological samples collected during pregnancy, at birth and at 3 years of age Phase Measurements Biological samples Baseline Oct 2012 ∼ May 2015 Mother Questionnaires: demographic characteristics/sociodemographic (education, occupational history, medical care status, menstruation and pregnancy history etc); personal lifestyle habits (smoking, alcohol, areca nut etc); diet and nutrient history; use of different plastic products; drinking water, house dampness, hair dyeing, cooking oil fumes, exercise activity); other Anthropometric measures: weight, height, blood pressure Third trimester: DNA, plasma, serum, urine Delivery: maternal stool, amniotic fluid, placenta After delivery: breast milk Newborn Neonate clinical examination: gender, gestational age (weeks), body length (cm), body weight (g), head circumference (cm), chest circumference (cm), Apgar Score, AGD ( ano-genital distance); neonatal neurobehavioural examination-Chinese version (tone and motor patterns, primitive reflexes, behavioural responses etc) Cord blood (DNA, serum), baby meconium Follow-up 2016∼ Mother Short questionnaire: current diet and nutrient intake, current frequent use of different plastic products and melamine-containing tableware etc DNA, serum, hair, buccal mucosa, urine Child Questionnaire: daily life habits (second-hand smoke, use of different plastic products, use of PVC floor etc); diet and nutrient history, medical history, behavioural activity (Child Behaviour Checklist for Ages 1.5-5 years; PSAI); other Anthropometric measures: weight, height Child cognitive assessment: Wechsler Preschool and Primary Scale of IntelligenceTM - Fourth Edition (WPPSI-IV) DNA, serum, hair, buccal mucosa, stool, urine Phase Measurements Biological samples Baseline Oct 2012 ∼ May 2015 Mother Questionnaires: demographic characteristics/sociodemographic (education, occupational history, medical care status, menstruation and pregnancy history etc); personal lifestyle habits (smoking, alcohol, areca nut etc); diet and nutrient history; use of different plastic products; drinking water, house dampness, hair dyeing, cooking oil fumes, exercise activity); other Anthropometric measures: weight, height, blood pressure Third trimester: DNA, plasma, serum, urine Delivery: maternal stool, amniotic fluid, placenta After delivery: breast milk Newborn Neonate clinical examination: gender, gestational age (weeks), body length (cm), body weight (g), head circumference (cm), chest circumference (cm), Apgar Score, AGD ( ano-genital distance); neonatal neurobehavioural examination-Chinese version (tone and motor patterns, primitive reflexes, behavioural responses etc) Cord blood (DNA, serum), baby meconium Follow-up 2016∼ Mother Short questionnaire: current diet and nutrient intake, current frequent use of different plastic products and melamine-containing tableware etc DNA, serum, hair, buccal mucosa, urine Child Questionnaire: daily life habits (second-hand smoke, use of different plastic products, use of PVC floor etc); diet and nutrient history, medical history, behavioural activity (Child Behaviour Checklist for Ages 1.5-5 years; PSAI); other Anthropometric measures: weight, height Child cognitive assessment: Wechsler Preschool and Primary Scale of IntelligenceTM - Fourth Edition (WPPSI-IV) DNA, serum, hair, buccal mucosa, stool, urine Table 2. Questionnaire data, physical parameters and biological samples collected during pregnancy, at birth and at 3 years of age Phase Measurements Biological samples Baseline Oct 2012 ∼ May 2015 Mother Questionnaires: demographic characteristics/sociodemographic (education, occupational history, medical care status, menstruation and pregnancy history etc); personal lifestyle habits (smoking, alcohol, areca nut etc); diet and nutrient history; use of different plastic products; drinking water, house dampness, hair dyeing, cooking oil fumes, exercise activity); other Anthropometric measures: weight, height, blood pressure Third trimester: DNA, plasma, serum, urine Delivery: maternal stool, amniotic fluid, placenta After delivery: breast milk Newborn Neonate clinical examination: gender, gestational age (weeks), body length (cm), body weight (g), head circumference (cm), chest circumference (cm), Apgar Score, AGD ( ano-genital distance); neonatal neurobehavioural examination-Chinese version (tone and motor patterns, primitive reflexes, behavioural responses etc) Cord blood (DNA, serum), baby meconium Follow-up 2016∼ Mother Short questionnaire: current diet and nutrient intake, current frequent use of different plastic products and melamine-containing tableware etc DNA, serum, hair, buccal mucosa, urine Child Questionnaire: daily life habits (second-hand smoke, use of different plastic products, use of PVC floor etc); diet and nutrient history, medical history, behavioural activity (Child Behaviour Checklist for Ages 1.5-5 years; PSAI); other Anthropometric measures: weight, height Child cognitive assessment: Wechsler Preschool and Primary Scale of IntelligenceTM - Fourth Edition (WPPSI-IV) DNA, serum, hair, buccal mucosa, stool, urine Phase Measurements Biological samples Baseline Oct 2012 ∼ May 2015 Mother Questionnaires: demographic characteristics/sociodemographic (education, occupational history, medical care status, menstruation and pregnancy history etc); personal lifestyle habits (smoking, alcohol, areca nut etc); diet and nutrient history; use of different plastic products; drinking water, house dampness, hair dyeing, cooking oil fumes, exercise activity); other Anthropometric measures: weight, height, blood pressure Third trimester: DNA, plasma, serum, urine Delivery: maternal stool, amniotic fluid, placenta After delivery: breast milk Newborn Neonate clinical examination: gender, gestational age (weeks), body length (cm), body weight (g), head circumference (cm), chest circumference (cm), Apgar Score, AGD ( ano-genital distance); neonatal neurobehavioural examination-Chinese version (tone and motor patterns, primitive reflexes, behavioural responses etc) Cord blood (DNA, serum), baby meconium Follow-up 2016∼ Mother Short questionnaire: current diet and nutrient intake, current frequent use of different plastic products and melamine-containing tableware etc DNA, serum, hair, buccal mucosa, urine Child Questionnaire: daily life habits (second-hand smoke, use of different plastic products, use of PVC floor etc); diet and nutrient history, medical history, behavioural activity (Child Behaviour Checklist for Ages 1.5-5 years; PSAI); other Anthropometric measures: weight, height Child cognitive assessment: Wechsler Preschool and Primary Scale of IntelligenceTM - Fourth Edition (WPPSI-IV) DNA, serum, hair, buccal mucosa, stool, urine With regard to sample collection, upon recruitment of the mothers during the third trimester, we collected blood and one-spot urine specimens. Later, during delivery, we collected samples of amniotic fluid, placenta, cord blood and baby meconium. We collected breast milk samples 2-5 weeks post after delivery. These samples were aliquoted and stored at -70°C for future studies (Table 2). Starting in October 2016, we began collecting one-spot urine samples from the mothers and their offspring when their children turned 3 years old. In addition, we also attempted to collect samples of their children’s hair, stool and serum. With hospital and participant agreement, we also measured 11 phthalate metabolites in samples collected from mothers in the first and second trimesters, if available (Supplementary Tables 1 and 2, available as Supplementary data at IJE online). What data were collected on the questionnaires? A trained interviewer at each hospital administered the first questionnaire to the pregnant mothers during their third trimester. The questionnaire collected demographic characteristics (age, height, weight, education, occupational history, medical care status, menstruation and pregnant history etc.), personal lifestyle habits (cigarette smoking, alcohol drinking, and areca nut chewing), diet and nutrient intake history, frequency of use of different plastic products and melamine-containing tableware, history of drinking water, environmental parameters for home and external environments including source of drinking water, house dampness, history of hair dyeing, cooking oil fume exposure, and exercise (Table 2). At delivery and 2–3 weeks after delivery, a similar but shortened form of the questionnaire was administered to monitor changes in parameters that could possibly change. Three years later, the detailed questionnaire was administered once more. A questionnaire about the children was administered to the mothers when their children turned 3 years old. A trained interviewer asked questions collecting demographic data (age, height, weight, medical care status etc.), daily life habits (second-hand smoke, use of different plastic products, use of PVC flooring etc.), diet and nutrient intake history, behaviour activity evaluation, including Child Behavior Checklist for Ages 11/2–5, Pre-School Activities Inventory (PSAI) etc., and child cognitive assessment using Wechsler Preschool and Primary Scale of IntelligenceTM - Fourth Edition (WPPSI-IV). What was measured? Urinary phthalate metabolites One-spot urine samples were taken from pregnant women in their third trimester to detect and measure concentrations of 11 phthalate metabolites using an online solid-phase extraction method coupled with high-performance liquid chromatography/tandem mass spectrometry with isotope dilution.8 The phthalate metabolites measured were five DEHP metabolites: MEHP [mono-(2-ethylhexyl) phthalate], MEOHP [mono-(2-ethyl-5-hydroxylhexyl) phthalate], MEHHP [mono-(2-ethyl-5-oxohexyl) phthalate], MECPP [mono(2-ethyl-5-carboxypentyl)phthalate] and MCMHP [mono(2-carboxymethylhexyl)phthalate]. The other phthalate metabolites were MnBP (mono-n-butyl phthalate), MiBP (mono-iso-butyl phthalate), MEP (monoethyl phthalate), MBzP (mono-benzyl phthalate), MMP (mono-methyl phthalate), and MiNP (mono-isononyl phthalate). The measurements were performed at a central analytical laboratory located at Taiwan’s National Health Research Institute (NHRI). The laboratory is certified by an international laboratory comparison programme (G-EQUAS 59). In addition, creatinine levels were measured. To do this, the urine samples were reacted with alkaline picrate to form a creatinine-picrate complex and quantified using spectrophotometry (Hitachi U-2000, Japan) set at 520 nm wavelength (Table 3). Table 3. Data collected on maternal and child exposure and health outcomes in the TIMCS cohort study to date, and planned for future Biomarkers Sample type Mother Children First trimester Second trimester Third trimester (baseline) 3–4 years Birth (cord blood) 3 years Environmental pollutants Acrylamide Urine ○ ○ ○ ○ NP Urine ● ● ● ○ BPA Urine ● ● ● ○ Pesticides Urine ○ ○ ○ ○ Metals Urine ○ ○ ● ○ Phthalate-11metabolites Urine ● ● ● ○ Melamine Urine ○ ○ ● ○ Creatinine Urine ● ● ● ○ Endogenous biochemistry Thyroid hormones (T3, T4, TSH, free T4) Serum ● ● Sex hormones (E2, TT, FSH, LH, PG) Serum ● ● SHBG, FTT, DHEA-S, TESBIO Renal function and urine routine tests(NAG, microalbumin) Urine ● ● ● Biochemical (insulin, AST, ALT, creatinine) Serum ● ● ● ● BUN, uric acid Albumin BUN, creatinine, uric acid Biochemical (CHOL, HDL, LDL, TG, serum iron-TIBC) ● Biochemical (glucose/sugar AC, fasting 8-h) Serum ● ● Blood routine tests(WBC, RBC, HbA1C, platelets etc) Blood ● ● ● CBC-1 Growth hormone (IGF1) Serum ● ● Immune (IgE) Serum ● ● ●a DNA Blood ● ● ● ● RNA Blood ● Biomarkers Sample type Mother Children First trimester Second trimester Third trimester (baseline) 3–4 years Birth (cord blood) 3 years Environmental pollutants Acrylamide Urine ○ ○ ○ ○ NP Urine ● ● ● ○ BPA Urine ● ● ● ○ Pesticides Urine ○ ○ ○ ○ Metals Urine ○ ○ ● ○ Phthalate-11metabolites Urine ● ● ● ○ Melamine Urine ○ ○ ● ○ Creatinine Urine ● ● ● ○ Endogenous biochemistry Thyroid hormones (T3, T4, TSH, free T4) Serum ● ● Sex hormones (E2, TT, FSH, LH, PG) Serum ● ● SHBG, FTT, DHEA-S, TESBIO Renal function and urine routine tests(NAG, microalbumin) Urine ● ● ● Biochemical (insulin, AST, ALT, creatinine) Serum ● ● ● ● BUN, uric acid Albumin BUN, creatinine, uric acid Biochemical (CHOL, HDL, LDL, TG, serum iron-TIBC) ● Biochemical (glucose/sugar AC, fasting 8-h) Serum ● ● Blood routine tests(WBC, RBC, HbA1C, platelets etc) Blood ● ● ● CBC-1 Growth hormone (IGF1) Serum ● ● Immune (IgE) Serum ● ● ●a DNA Blood ● ● ● ● RNA Blood ● ● represents finished measurement or finished part of measurement; ○ represents will be finished in the future. a Including MAST CLA Allergy Test. Table 3. Data collected on maternal and child exposure and health outcomes in the TIMCS cohort study to date, and planned for future Biomarkers Sample type Mother Children First trimester Second trimester Third trimester (baseline) 3–4 years Birth (cord blood) 3 years Environmental pollutants Acrylamide Urine ○ ○ ○ ○ NP Urine ● ● ● ○ BPA Urine ● ● ● ○ Pesticides Urine ○ ○ ○ ○ Metals Urine ○ ○ ● ○ Phthalate-11metabolites Urine ● ● ● ○ Melamine Urine ○ ○ ● ○ Creatinine Urine ● ● ● ○ Endogenous biochemistry Thyroid hormones (T3, T4, TSH, free T4) Serum ● ● Sex hormones (E2, TT, FSH, LH, PG) Serum ● ● SHBG, FTT, DHEA-S, TESBIO Renal function and urine routine tests(NAG, microalbumin) Urine ● ● ● Biochemical (insulin, AST, ALT, creatinine) Serum ● ● ● ● BUN, uric acid Albumin BUN, creatinine, uric acid Biochemical (CHOL, HDL, LDL, TG, serum iron-TIBC) ● Biochemical (glucose/sugar AC, fasting 8-h) Serum ● ● Blood routine tests(WBC, RBC, HbA1C, platelets etc) Blood ● ● ● CBC-1 Growth hormone (IGF1) Serum ● ● Immune (IgE) Serum ● ● ●a DNA Blood ● ● ● ● RNA Blood ● Biomarkers Sample type Mother Children First trimester Second trimester Third trimester (baseline) 3–4 years Birth (cord blood) 3 years Environmental pollutants Acrylamide Urine ○ ○ ○ ○ NP Urine ● ● ● ○ BPA Urine ● ● ● ○ Pesticides Urine ○ ○ ○ ○ Metals Urine ○ ○ ● ○ Phthalate-11metabolites Urine ● ● ● ○ Melamine Urine ○ ○ ● ○ Creatinine Urine ● ● ● ○ Endogenous biochemistry Thyroid hormones (T3, T4, TSH, free T4) Serum ● ● Sex hormones (E2, TT, FSH, LH, PG) Serum ● ● SHBG, FTT, DHEA-S, TESBIO Renal function and urine routine tests(NAG, microalbumin) Urine ● ● ● Biochemical (insulin, AST, ALT, creatinine) Serum ● ● ● ● BUN, uric acid Albumin BUN, creatinine, uric acid Biochemical (CHOL, HDL, LDL, TG, serum iron-TIBC) ● Biochemical (glucose/sugar AC, fasting 8-h) Serum ● ● Blood routine tests(WBC, RBC, HbA1C, platelets etc) Blood ● ● ● CBC-1 Growth hormone (IGF1) Serum ● ● Immune (IgE) Serum ● ● ●a DNA Blood ● ● ● ● RNA Blood ● ● represents finished measurement or finished part of measurement; ○ represents will be finished in the future. a Including MAST CLA Allergy Test. Daily intake levels of DEHP, DEP, DnBP, DiBP and BBzP in each pregnant woman were estimated using a creatinine excretion-based model.2,9 The five urinary DEHP metabolites (MEHP, MEOHP, MEHHP, MECPP and MCMHP) were used to estimate daily intake of DEHP. MEP, MnBP, MiBP and MBzP were used to estimate daily intake of DEP, DnBP, DiBP and BBzP, respectively. The creatinine excretion-based model of DEHP was calculated as follows: DEHP (µg/kg/day)=[UEsum(mmol/g Cr)×CE (g Cr/kgbody weight/day)/(FUE×1000)]× MWDEHP where UEsum, CE, FUE and MWDEHP represent the molar urinary excretion sum of the five measured urinary oxidative DEHP metabolites, creatinine excretion rate, molar fraction and molecular weight of DEHP, respectively. Creatinine excretion rate (CE) was set at 18 mg/kg/day for women.10,11 The FUE values were 0.059 for MEHP, 0.233 for MEHHP, 0.150 for MEOHP, 0.185 for MECPP and 0.042 for MCMHP.12 The FUE of the others were 0.690 for MEP, 0.690 for MnBP, 0.703 for MiBP and 0.730 for MBzP, respectively9,13,14 (Table 4). Table 4. Comparison of median (range) of phthalate metabolites (µg/g Cr) among pregnant women (third trimester) in different studies. (a) in Taiwan (b) in other countries (a) Phthalate metabolites (µg/g Cr)1 This study (Taiwan) (n = 1631) 2012–15 (Wu et al., 2017) Taiwan (Taipei) (n = 180) 2012–15 (Tsai et al., 2017) Taiwan (Taipei) (n = 112) 2010–11 (Tsai et al., 2017) Taiwan (Kaohsiung) (n = 148) 2009–10 (Kuo et al., 2015) Taiwan (Taichung) (n = 100) 2001–02 (Lin et al., 2011) Taiwan (Tainan) (n = 155) 2000–01 (Lin et al. 2011) MEHP 4.91 (0.06–470.45) 4.16 (0.06–88.13) 26.27 (0.25–274.59) 11.92 (3.09–298.82) 16.37 (0.38–353.9) 19.1 (3.73–193) MEOHP 12.59 (0.17–713.19) 9.32 (0.15–118.07) 14.42 (1.60–140.70) 20.49 (4.54–246.07) 29.5 (8.06–2663) 25.6 (ND-801) MEHHP 14.51 (0.09–836.20) 11.05 (0.08–327.03) 15.96 (0.64–253.29) 21.73 (5.00–303.38) 33.2 (7.49–2114) 19.7 (ND-407) MECPP 20.56 (0.01–816.27) 16.88 (0.01–280.04) 23.13 (3.56–306.95) – 44.69 (5.69–3545) – MCMHP 5.42 (0.01–189.09) – – – 10.19 (1.5–756) – MnBP 21.5 (0.13–1607.6) 17.80 (0.13–563.16) 35.28 (1.59–491.16) 37.81 (8.85–663.03) 87.49 (26.8–569) – MiBP 11.28 (0.11–289.36) 9.22 (0.26–248.68) 30.17 (0.13–10184.24) 20.21 (4.68–493.0) 15.19 (2.45–165) – MBzP 0.47 (0.03–250.51) 0.86 (0.03–49.20) 2.22 (0.36–254.04) 1.35 (0.23–57.05) 2.07 (0.08–235) 15.6 (ND-104) MEP 18.34 (0.04–18774) 16.93 (0.06–1630.43) 36.89 (3.56–2335.89) 34.51 (2.85–9291.7) – 56.0 (9.33–863) MMP 8.75 (0.03–337.97) 5.77 (0.03–82.74) 5.37 (0.25–33.04) 7.97 (ND-91.60) – 54.7 (ND-728) MiNP ND – – ND – – (a) Phthalate metabolites (µg/g Cr)1 This study (Taiwan) (n = 1631) 2012–15 (Wu et al., 2017) Taiwan (Taipei) (n = 180) 2012–15 (Tsai et al., 2017) Taiwan (Taipei) (n = 112) 2010–11 (Tsai et al., 2017) Taiwan (Kaohsiung) (n = 148) 2009–10 (Kuo et al., 2015) Taiwan (Taichung) (n = 100) 2001–02 (Lin et al., 2011) Taiwan (Tainan) (n = 155) 2000–01 (Lin et al. 2011) MEHP 4.91 (0.06–470.45) 4.16 (0.06–88.13) 26.27 (0.25–274.59) 11.92 (3.09–298.82) 16.37 (0.38–353.9) 19.1 (3.73–193) MEOHP 12.59 (0.17–713.19) 9.32 (0.15–118.07) 14.42 (1.60–140.70) 20.49 (4.54–246.07) 29.5 (8.06–2663) 25.6 (ND-801) MEHHP 14.51 (0.09–836.20) 11.05 (0.08–327.03) 15.96 (0.64–253.29) 21.73 (5.00–303.38) 33.2 (7.49–2114) 19.7 (ND-407) MECPP 20.56 (0.01–816.27) 16.88 (0.01–280.04) 23.13 (3.56–306.95) – 44.69 (5.69–3545) – MCMHP 5.42 (0.01–189.09) – – – 10.19 (1.5–756) – MnBP 21.5 (0.13–1607.6) 17.80 (0.13–563.16) 35.28 (1.59–491.16) 37.81 (8.85–663.03) 87.49 (26.8–569) – MiBP 11.28 (0.11–289.36) 9.22 (0.26–248.68) 30.17 (0.13–10184.24) 20.21 (4.68–493.0) 15.19 (2.45–165) – MBzP 0.47 (0.03–250.51) 0.86 (0.03–49.20) 2.22 (0.36–254.04) 1.35 (0.23–57.05) 2.07 (0.08–235) 15.6 (ND-104) MEP 18.34 (0.04–18774) 16.93 (0.06–1630.43) 36.89 (3.56–2335.89) 34.51 (2.85–9291.7) – 56.0 (9.33–863) MMP 8.75 (0.03–337.97) 5.77 (0.03–82.74) 5.37 (0.25–33.04) 7.97 (ND-91.60) – 54.7 (ND-728) MiNP ND – – ND – – (b) Phthalate metabolites (µg/g Cr)1 China (n = 293) 2012–14 Zhu et al., 2016 Spanish (n = 391) 2004–06 Valvi et al., 2015 Polish (n = 165) 2007–08 (Polanska et al., 2014) France (n = 279) 2007 (Zeman et al., 2013) Japan (n = 50) 2005–06 (Suzuki et al., 2009) Israel (n = 19) 2006 (Berman et al., 2009) Netherlands (n = 99) 2004–06 (Ye et al., 2008) MEHP 3.82 (<LOD–76.5)a 9.3 (0.37–183) 0.2 (0.02–4.3) 17.9 (1.4–1358.9) 5.15 (ND-67.8) 7.0 (ND-40.8) 9.9 (ND-321.0) MEOHP 8.78 (2.53–48.5)a 18.5 (0.6–701) 1.6 (0.04–140) – 11.9 (3.46-174) 17.5 (5.0–129.4) 20.9 (5.3–386.0) MEHHP 10.1 (2.97–57.2)a 23.0 (0.7–932) 2.73 (0.02–431) – 10.7 (3.9–164) 24.3 (5.3–133.8) 20.3 (3.7–371.0) MECPP 12.8 (3.96–71.3)a 34.5 (2.4–1356) – – – 41.1 (13.7–193.4) 25.8 (8.1–317.0) MCMHP – 41.8 (2.4–2014) – – – – 9.1 (1.6–73.6) MnBP 107.0 (25.5–514)a 28.1 (0.6–1652) 4.6 (0.02–846) 45.5 (4.8–1269.0) 66.6 (11.1–211) – 62.2 (15.3–351.0) MiBP – 29.8 (1.9–623) 11.1 (0.02–1239) 68.7 (7.8–1471.8) – 27.7 (ND-52.7) 57.1 (14.4–640.0) MBzP – 10.0 (0.8–476) 0.05 (0.02–6.7) 13.6 (2.0–705.1) 4.37 (0.69–109) 9.6 (0.45–108.8) 11.7 (3.0–405.0) MEP 9.89 (1.91–54.0)a 386 (0.6–6597) 22.7 (1.7–4235) 34.3 ( 0–7593.8) 9.4 (1.25–1430) 140.5 (29.4–14956) 222 (ND-7160) MMP – – – – 8.15 (2.16–714) – ND (ND-197) MiNP – – – <5.0 ND (ND-3.5) – – (b) Phthalate metabolites (µg/g Cr)1 China (n = 293) 2012–14 Zhu et al., 2016 Spanish (n = 391) 2004–06 Valvi et al., 2015 Polish (n = 165) 2007–08 (Polanska et al., 2014) France (n = 279) 2007 (Zeman et al., 2013) Japan (n = 50) 2005–06 (Suzuki et al., 2009) Israel (n = 19) 2006 (Berman et al., 2009) Netherlands (n = 99) 2004–06 (Ye et al., 2008) MEHP 3.82 (<LOD–76.5)a 9.3 (0.37–183) 0.2 (0.02–4.3) 17.9 (1.4–1358.9) 5.15 (ND-67.8) 7.0 (ND-40.8) 9.9 (ND-321.0) MEOHP 8.78 (2.53–48.5)a 18.5 (0.6–701) 1.6 (0.04–140) – 11.9 (3.46-174) 17.5 (5.0–129.4) 20.9 (5.3–386.0) MEHHP 10.1 (2.97–57.2)a 23.0 (0.7–932) 2.73 (0.02–431) – 10.7 (3.9–164) 24.3 (5.3–133.8) 20.3 (3.7–371.0) MECPP 12.8 (3.96–71.3)a 34.5 (2.4–1356) – – – 41.1 (13.7–193.4) 25.8 (8.1–317.0) MCMHP – 41.8 (2.4–2014) – – – – 9.1 (1.6–73.6) MnBP 107.0 (25.5–514)a 28.1 (0.6–1652) 4.6 (0.02–846) 45.5 (4.8–1269.0) 66.6 (11.1–211) – 62.2 (15.3–351.0) MiBP – 29.8 (1.9–623) 11.1 (0.02–1239) 68.7 (7.8–1471.8) – 27.7 (ND-52.7) 57.1 (14.4–640.0) MBzP – 10.0 (0.8–476) 0.05 (0.02–6.7) 13.6 (2.0–705.1) 4.37 (0.69–109) 9.6 (0.45–108.8) 11.7 (3.0–405.0) MEP 9.89 (1.91–54.0)a 386 (0.6–6597) 22.7 (1.7–4235) 34.3 ( 0–7593.8) 9.4 (1.25–1430) 140.5 (29.4–14956) 222 (ND-7160) MMP – – – – 8.15 (2.16–714) – ND (ND-197) MiNP – – – <5.0 ND (ND-3.5) – – a Median (5th-95th). Table 4. Comparison of median (range) of phthalate metabolites (µg/g Cr) among pregnant women (third trimester) in different studies. (a) in Taiwan (b) in other countries (a) Phthalate metabolites (µg/g Cr)1 This study (Taiwan) (n = 1631) 2012–15 (Wu et al., 2017) Taiwan (Taipei) (n = 180) 2012–15 (Tsai et al., 2017) Taiwan (Taipei) (n = 112) 2010–11 (Tsai et al., 2017) Taiwan (Kaohsiung) (n = 148) 2009–10 (Kuo et al., 2015) Taiwan (Taichung) (n = 100) 2001–02 (Lin et al., 2011) Taiwan (Tainan) (n = 155) 2000–01 (Lin et al. 2011) MEHP 4.91 (0.06–470.45) 4.16 (0.06–88.13) 26.27 (0.25–274.59) 11.92 (3.09–298.82) 16.37 (0.38–353.9) 19.1 (3.73–193) MEOHP 12.59 (0.17–713.19) 9.32 (0.15–118.07) 14.42 (1.60–140.70) 20.49 (4.54–246.07) 29.5 (8.06–2663) 25.6 (ND-801) MEHHP 14.51 (0.09–836.20) 11.05 (0.08–327.03) 15.96 (0.64–253.29) 21.73 (5.00–303.38) 33.2 (7.49–2114) 19.7 (ND-407) MECPP 20.56 (0.01–816.27) 16.88 (0.01–280.04) 23.13 (3.56–306.95) – 44.69 (5.69–3545) – MCMHP 5.42 (0.01–189.09) – – – 10.19 (1.5–756) – MnBP 21.5 (0.13–1607.6) 17.80 (0.13–563.16) 35.28 (1.59–491.16) 37.81 (8.85–663.03) 87.49 (26.8–569) – MiBP 11.28 (0.11–289.36) 9.22 (0.26–248.68) 30.17 (0.13–10184.24) 20.21 (4.68–493.0) 15.19 (2.45–165) – MBzP 0.47 (0.03–250.51) 0.86 (0.03–49.20) 2.22 (0.36–254.04) 1.35 (0.23–57.05) 2.07 (0.08–235) 15.6 (ND-104) MEP 18.34 (0.04–18774) 16.93 (0.06–1630.43) 36.89 (3.56–2335.89) 34.51 (2.85–9291.7) – 56.0 (9.33–863) MMP 8.75 (0.03–337.97) 5.77 (0.03–82.74) 5.37 (0.25–33.04) 7.97 (ND-91.60) – 54.7 (ND-728) MiNP ND – – ND – – (a) Phthalate metabolites (µg/g Cr)1 This study (Taiwan) (n = 1631) 2012–15 (Wu et al., 2017) Taiwan (Taipei) (n = 180) 2012–15 (Tsai et al., 2017) Taiwan (Taipei) (n = 112) 2010–11 (Tsai et al., 2017) Taiwan (Kaohsiung) (n = 148) 2009–10 (Kuo et al., 2015) Taiwan (Taichung) (n = 100) 2001–02 (Lin et al., 2011) Taiwan (Tainan) (n = 155) 2000–01 (Lin et al. 2011) MEHP 4.91 (0.06–470.45) 4.16 (0.06–88.13) 26.27 (0.25–274.59) 11.92 (3.09–298.82) 16.37 (0.38–353.9) 19.1 (3.73–193) MEOHP 12.59 (0.17–713.19) 9.32 (0.15–118.07) 14.42 (1.60–140.70) 20.49 (4.54–246.07) 29.5 (8.06–2663) 25.6 (ND-801) MEHHP 14.51 (0.09–836.20) 11.05 (0.08–327.03) 15.96 (0.64–253.29) 21.73 (5.00–303.38) 33.2 (7.49–2114) 19.7 (ND-407) MECPP 20.56 (0.01–816.27) 16.88 (0.01–280.04) 23.13 (3.56–306.95) – 44.69 (5.69–3545) – MCMHP 5.42 (0.01–189.09) – – – 10.19 (1.5–756) – MnBP 21.5 (0.13–1607.6) 17.80 (0.13–563.16) 35.28 (1.59–491.16) 37.81 (8.85–663.03) 87.49 (26.8–569) – MiBP 11.28 (0.11–289.36) 9.22 (0.26–248.68) 30.17 (0.13–10184.24) 20.21 (4.68–493.0) 15.19 (2.45–165) – MBzP 0.47 (0.03–250.51) 0.86 (0.03–49.20) 2.22 (0.36–254.04) 1.35 (0.23–57.05) 2.07 (0.08–235) 15.6 (ND-104) MEP 18.34 (0.04–18774) 16.93 (0.06–1630.43) 36.89 (3.56–2335.89) 34.51 (2.85–9291.7) – 56.0 (9.33–863) MMP 8.75 (0.03–337.97) 5.77 (0.03–82.74) 5.37 (0.25–33.04) 7.97 (ND-91.60) – 54.7 (ND-728) MiNP ND – – ND – – (b) Phthalate metabolites (µg/g Cr)1 China (n = 293) 2012–14 Zhu et al., 2016 Spanish (n = 391) 2004–06 Valvi et al., 2015 Polish (n = 165) 2007–08 (Polanska et al., 2014) France (n = 279) 2007 (Zeman et al., 2013) Japan (n = 50) 2005–06 (Suzuki et al., 2009) Israel (n = 19) 2006 (Berman et al., 2009) Netherlands (n = 99) 2004–06 (Ye et al., 2008) MEHP 3.82 (<LOD–76.5)a 9.3 (0.37–183) 0.2 (0.02–4.3) 17.9 (1.4–1358.9) 5.15 (ND-67.8) 7.0 (ND-40.8) 9.9 (ND-321.0) MEOHP 8.78 (2.53–48.5)a 18.5 (0.6–701) 1.6 (0.04–140) – 11.9 (3.46-174) 17.5 (5.0–129.4) 20.9 (5.3–386.0) MEHHP 10.1 (2.97–57.2)a 23.0 (0.7–932) 2.73 (0.02–431) – 10.7 (3.9–164) 24.3 (5.3–133.8) 20.3 (3.7–371.0) MECPP 12.8 (3.96–71.3)a 34.5 (2.4–1356) – – – 41.1 (13.7–193.4) 25.8 (8.1–317.0) MCMHP – 41.8 (2.4–2014) – – – – 9.1 (1.6–73.6) MnBP 107.0 (25.5–514)a 28.1 (0.6–1652) 4.6 (0.02–846) 45.5 (4.8–1269.0) 66.6 (11.1–211) – 62.2 (15.3–351.0) MiBP – 29.8 (1.9–623) 11.1 (0.02–1239) 68.7 (7.8–1471.8) – 27.7 (ND-52.7) 57.1 (14.4–640.0) MBzP – 10.0 (0.8–476) 0.05 (0.02–6.7) 13.6 (2.0–705.1) 4.37 (0.69–109) 9.6 (0.45–108.8) 11.7 (3.0–405.0) MEP 9.89 (1.91–54.0)a 386 (0.6–6597) 22.7 (1.7–4235) 34.3 ( 0–7593.8) 9.4 (1.25–1430) 140.5 (29.4–14956) 222 (ND-7160) MMP – – – – 8.15 (2.16–714) – ND (ND-197) MiNP – – – <5.0 ND (ND-3.5) – – (b) Phthalate metabolites (µg/g Cr)1 China (n = 293) 2012–14 Zhu et al., 2016 Spanish (n = 391) 2004–06 Valvi et al., 2015 Polish (n = 165) 2007–08 (Polanska et al., 2014) France (n = 279) 2007 (Zeman et al., 2013) Japan (n = 50) 2005–06 (Suzuki et al., 2009) Israel (n = 19) 2006 (Berman et al., 2009) Netherlands (n = 99) 2004–06 (Ye et al., 2008) MEHP 3.82 (<LOD–76.5)a 9.3 (0.37–183) 0.2 (0.02–4.3) 17.9 (1.4–1358.9) 5.15 (ND-67.8) 7.0 (ND-40.8) 9.9 (ND-321.0) MEOHP 8.78 (2.53–48.5)a 18.5 (0.6–701) 1.6 (0.04–140) – 11.9 (3.46-174) 17.5 (5.0–129.4) 20.9 (5.3–386.0) MEHHP 10.1 (2.97–57.2)a 23.0 (0.7–932) 2.73 (0.02–431) – 10.7 (3.9–164) 24.3 (5.3–133.8) 20.3 (3.7–371.0) MECPP 12.8 (3.96–71.3)a 34.5 (2.4–1356) – – – 41.1 (13.7–193.4) 25.8 (8.1–317.0) MCMHP – 41.8 (2.4–2014) – – – – 9.1 (1.6–73.6) MnBP 107.0 (25.5–514)a 28.1 (0.6–1652) 4.6 (0.02–846) 45.5 (4.8–1269.0) 66.6 (11.1–211) – 62.2 (15.3–351.0) MiBP – 29.8 (1.9–623) 11.1 (0.02–1239) 68.7 (7.8–1471.8) – 27.7 (ND-52.7) 57.1 (14.4–640.0) MBzP – 10.0 (0.8–476) 0.05 (0.02–6.7) 13.6 (2.0–705.1) 4.37 (0.69–109) 9.6 (0.45–108.8) 11.7 (3.0–405.0) MEP 9.89 (1.91–54.0)a 386 (0.6–6597) 22.7 (1.7–4235) 34.3 ( 0–7593.8) 9.4 (1.25–1430) 140.5 (29.4–14956) 222 (ND-7160) MMP – – – – 8.15 (2.16–714) – ND (ND-197) MiNP – – – <5.0 ND (ND-3.5) – – a Median (5th-95th). Estimated daily intakes were used to calculate the hazard quotient (HQ) and then hazard index (HI) in order estimate each participant’s cumulative risk of phthalate exposure. The equation for doing this has been recently established, and described follows:15,16 HQ=DI (μg/kg/day) /Reference limit value (μg/kg/day)HI=ΣHQ where the reference limit values (RLV) are the TDI or RfD (Table 4). The RLVs selected for DEHP, BBzP, DBP(DnBP) and DEP were established by the European Food Safety Authority (EFSA) and are the same as those listed for Taiwan. They were 50, 500, 10 and 500 μg/kg/day, respectively. The RfDs for these phthalates were 20, 200, 100, 800 μg/kg/day, values established by the United States Environmental Protection Agency (US EPA) for these phthalates. Because there is no tolerable daily intake (TDI) or reference dose (RfD) for DiBP, the DnBP value used in this study was based on analogy assignment, 10 and 100 μg/kg/day, respectively.17 In addition, as the EFSA did not provide a TDI for DEP, the value we used was from the World Health Organization, 500 μg/kg/day.18 As suggested by Koch et al,15 we restricted our analyses of phthalates to those that had TDIs or RfD with similar toxicological endpoints on anti-androgenic effects, as follows16 (Table 5): HITDI= HQDnBP TDI+ HQDiBP TDI+ HQDEHP TDI+ HQBBzP TDI+ HQDEP TDIHIRfD= HQDnBP RfD+ HQDiBP RfD+ HQDEHP RfD+ HQBBzP RfD+ HQDEP RfD Table 5. Daily pthalate intake in pregnant women and percent above the threshold of TDI from US-/EFSA in Taiwan (n = 1631) Pthalate intake Percentile RfD/TDI (US-/EFSA) > US- > EFSA (μg/kg/day) n Mean ± SD Minimum 5th 25th 50th 75th 95th Maximum n (%) DEP 1631 2.61±19.17 0.001 0.005 0.22 0.55 1.58 8.77 560.56 800/500a 0 1 (<0.01) DnBP 1.09 ± 2.06 0.004 0.21 0.43 0.70 1.12 2.79 52.52 100/10 0 14 (0.01) DiBP 0.55 ± 0.71 0.003 0.10 0.23 0.36 0.61 1.52 9.28 −(100/10) 0 0 BBzP 0.06 ± 0.24 0.001 0.002 0.004 0.01 0.06 0.19 7.53 200/500 0 0 DEHP 3.03 ± 4.69 0.043 0.64 1.32 2.03 3.23 7.47 97.22 20/50 21 (1.3) 3 (0.2) Pthalate intake Percentile RfD/TDI (US-/EFSA) > US- > EFSA (μg/kg/day) n Mean ± SD Minimum 5th 25th 50th 75th 95th Maximum n (%) DEP 1631 2.61±19.17 0.001 0.005 0.22 0.55 1.58 8.77 560.56 800/500a 0 1 (<0.01) DnBP 1.09 ± 2.06 0.004 0.21 0.43 0.70 1.12 2.79 52.52 100/10 0 14 (0.01) DiBP 0.55 ± 0.71 0.003 0.10 0.23 0.36 0.61 1.52 9.28 −(100/10) 0 0 BBzP 0.06 ± 0.24 0.001 0.002 0.004 0.01 0.06 0.19 7.53 200/500 0 0 DEHP 3.03 ± 4.69 0.043 0.64 1.32 2.03 3.23 7.47 97.22 20/50 21 (1.3) 3 (0.2) a The TDI value for DEP was from the World Health Organization (WHO, 2003). Table 5. Daily pthalate intake in pregnant women and percent above the threshold of TDI from US-/EFSA in Taiwan (n = 1631) Pthalate intake Percentile RfD/TDI (US-/EFSA) > US- > EFSA (μg/kg/day) n Mean ± SD Minimum 5th 25th 50th 75th 95th Maximum n (%) DEP 1631 2.61±19.17 0.001 0.005 0.22 0.55 1.58 8.77 560.56 800/500a 0 1 (<0.01) DnBP 1.09 ± 2.06 0.004 0.21 0.43 0.70 1.12 2.79 52.52 100/10 0 14 (0.01) DiBP 0.55 ± 0.71 0.003 0.10 0.23 0.36 0.61 1.52 9.28 −(100/10) 0 0 BBzP 0.06 ± 0.24 0.001 0.002 0.004 0.01 0.06 0.19 7.53 200/500 0 0 DEHP 3.03 ± 4.69 0.043 0.64 1.32 2.03 3.23 7.47 97.22 20/50 21 (1.3) 3 (0.2) Pthalate intake Percentile RfD/TDI (US-/EFSA) > US- > EFSA (μg/kg/day) n Mean ± SD Minimum 5th 25th 50th 75th 95th Maximum n (%) DEP 1631 2.61±19.17 0.001 0.005 0.22 0.55 1.58 8.77 560.56 800/500a 0 1 (<0.01) DnBP 1.09 ± 2.06 0.004 0.21 0.43 0.70 1.12 2.79 52.52 100/10 0 14 (0.01) DiBP 0.55 ± 0.71 0.003 0.10 0.23 0.36 0.61 1.52 9.28 −(100/10) 0 0 BBzP 0.06 ± 0.24 0.001 0.002 0.004 0.01 0.06 0.19 7.53 200/500 0 0 DEHP 3.03 ± 4.69 0.043 0.64 1.32 2.03 3.23 7.47 97.22 20/50 21 (1.3) 3 (0.2) a The TDI value for DEP was from the World Health Organization (WHO, 2003). In addition to having measured urinary phthalate metabolites, we also plan to measure other environmental hazards in the stored urine specimens. These include organophosphate pesticides, nonylphenol, bisphenol A, heavy metals, melamine and acrylamide (Table 3). Biochemical data for mothers upon recruitment and for newborns at birth Clinical biochemistry concentrations and those of other important biomarkers collected during the third trimester of the women in this study, as well as those collected from the cord blood of their newborn, were analysed in a central clinical laboratory in Taipei (Tables 2 and 3). That laboratory is officially accredited by Taiwan Accreditation Foundation which uses the same accreditation criteria as those outlined by ISO 15189: 2007. This certification was effective between 16 March 2015 and 15 March 2018 (Certificate No. L1447–150325). The baseline blood analysis for the mothers included the following measurements: (i) thyroid hormones and sex hormones—thyroxine (T4), triiodothyronine (T3), thyroid-stimulating hormone (TSH), free thyroxine (free T4), stradiol (E2), testosterone (TT), progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH); (ii) renal function indicators—blood urea nitrogen (BUN), uric acid and creatinine; (iii) biochemical indicators—aspartate aminotransferase (AST), alanine aminotransferase (ALT), sugar AC, insulin, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglyceride; and (iv) routine blood examination—white blood cells (WBC), red blood cells (RBC), platelets, haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), neutrophils, lymphocytes, monocytes, eosinophils and basophils (Table 3). The baseline blood measurements for newborn cord blood included the following: (i) thyroid hormones and sex hormones—thyroxine (T4), triiodothyronine (T3), thyroid-stimulating hormone (TSH), free thyroxine (free T4), estradiol (E2), testosterone (TT), progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), free testosterone, albumin, dehydroepiandrosterone sulphate (DHEA-S) and bioavailable testosterone (TESBIO); (ii) growth hormone—insulin-like growth factor-1(IGF1); (ii) immunoglobulin—immunoglobulin E (IgE), multiple allergosorbent chemiluminescent assay (MAST CLA) allergy test; and (iv) routine blood examination—white blood cells (WBC), red blood cells (RBC), platelets, haemoglobin, hamatocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), neutrophils, lymphocytes, monocytes, eosinophils and basophils. What has it found? Key baseline findings Because urinary MiNP, which represents the primary metabolites of DINP (Di-isononyl phthalate), was not detectable in 97.0% (n = 1582/1631), we only present the results of the other 10 urinary phthalate metabolites. The median levels without creatinine correction (ng/ml) for these 10 urinary phthalate metabolites in the third trimester were: 3.35 for MEHP, 8.42 for MEOHP, 10.07 for MEHHP, 14.18 for MECPP, 3.79 for MCMHP, 14.64 for MnBP, 7.56 for MiBP, 0.06 for MBzP, 4.33 for MEP and 5.69 for MMP (Supplementary Table 3, available as Supplementary data at IJE online). After urinary creatinine correction, their median levels (μg/g creatinine) were: 4.91 for MEHP, 12.59 for MEOHP, 14.51 for MEHHP, 20.56 for MECPP, 5.42 for MCMHP, 21.50 for MnBP, 11.28 for MiBP, 0.47 for MBzP, 18.34 for MEP and 8.75 for MMP (Supplementary Table 4, available as Supplementary data at IJE online; Figure 2). In this study, the three metabolites with highest recorded urinary concentrations were MnBP, MECPP and MEP (Supplementary Table 4, available as Supplementary data at IJE online; Figure 2). Figure 2 View largeDownload slide Ten phthalate metabolites of pregnant women in the third trimester from four areas of Taiwan, corrected by creatinine (n = 1631). Figure 2 View largeDownload slide Ten phthalate metabolites of pregnant women in the third trimester from four areas of Taiwan, corrected by creatinine (n = 1631). The concentrations of urinary phthalate metabolites found in this study were lower than those reported by previous studies from Taiwan,3,5,6 suggesting that the phthalate exposures in the general population in Taiwan significantly decreased after the 2011 phthalate food scandal (Table 4). We compared these findings with those of other countries in the same situation, in the third trimester of pregnant women, and found urinary phthalate metabolite concentrations in this study to be generally lower than those reported for European countries,19–23 but generally higher than those reported for Japan.24 Mean and median daily DEHP intake of the participating mothers in the third trimester was 3.03 and 2.03 μg/kg/day, respectively (Table 5). Compared with the recommended tolerable daily intake (TDI) level for DEHP defined by the U.S. Environmental Protection Agency (0.02 mg/kg/day) and the European Food Safety Authority (0.05 mg/kg/day), we found intake of 21 (1.3%) of the women we studied to be above 20 μg/kg/day and in three (0.2%) of them to be above 50 μg/kg/day (Table 5). Based on EFSA TDI, the median HI level, the summation of HQs in the pregnant women was 0.16 (Table 6), a value higher than that reported by a study of pregnant Danish women (0.06) (8–30 gestational weeks)25 and lower than that reported by a study of pregnant Chinese women (0.358).16 Table 6. Hazard quotients (HQ) and hazard indexes (HI) based on TDI (EFSA) and RfD (US EPA) for pregnant women (n = 1631) Phthalate HQ based on EFSA TDI >1 HQ based on US EPA RfD >1 Minimum 25th 50th 95th Maximum n (%) Minimum 25th 50th 95th Maximum n (%) DEP <0.0001 0.0004 0.0011 0.0175 1.1211 1 (0.06) <0.0001 0.0003 0.0007 0.0110 0.7007 0 DnBP 0.0004 0.0430 0.0702 0.2791 5.2524 14 (0.9) <0.0001 0.0043 0.0070 0.0279 0.5252 0 DiBP 0.0003 0.0233 0.0362 0.1521 0.9279 0 <0.0001 0.0023 0.0036 0.0152 0.0928 0 BBzP <0.0001 <0.0001 <0.0001 0.0004 0.0151 0 <0.0001 <0.0001 <0.0001 0.0009 0.0376 0 DEHP 0.0009 0.0265 0.0405 0.1494 1.9443 3 (0.18) 0.0021 0.06621 0.1014 0.3734 4.8608 21 (1.3) HI 0.0036 0.1150 0.1684 0.5517 5.5422 30 (1.8) 0.0029 0.0779 0.1198 0.4116 4.8848 21 (1.3) Phthalate HQ based on EFSA TDI >1 HQ based on US EPA RfD >1 Minimum 25th 50th 95th Maximum n (%) Minimum 25th 50th 95th Maximum n (%) DEP <0.0001 0.0004 0.0011 0.0175 1.1211 1 (0.06) <0.0001 0.0003 0.0007 0.0110 0.7007 0 DnBP 0.0004 0.0430 0.0702 0.2791 5.2524 14 (0.9) <0.0001 0.0043 0.0070 0.0279 0.5252 0 DiBP 0.0003 0.0233 0.0362 0.1521 0.9279 0 <0.0001 0.0023 0.0036 0.0152 0.0928 0 BBzP <0.0001 <0.0001 <0.0001 0.0004 0.0151 0 <0.0001 <0.0001 <0.0001 0.0009 0.0376 0 DEHP 0.0009 0.0265 0.0405 0.1494 1.9443 3 (0.18) 0.0021 0.06621 0.1014 0.3734 4.8608 21 (1.3) HI 0.0036 0.1150 0.1684 0.5517 5.5422 30 (1.8) 0.0029 0.0779 0.1198 0.4116 4.8848 21 (1.3) Table 6. Hazard quotients (HQ) and hazard indexes (HI) based on TDI (EFSA) and RfD (US EPA) for pregnant women (n = 1631) Phthalate HQ based on EFSA TDI >1 HQ based on US EPA RfD >1 Minimum 25th 50th 95th Maximum n (%) Minimum 25th 50th 95th Maximum n (%) DEP <0.0001 0.0004 0.0011 0.0175 1.1211 1 (0.06) <0.0001 0.0003 0.0007 0.0110 0.7007 0 DnBP 0.0004 0.0430 0.0702 0.2791 5.2524 14 (0.9) <0.0001 0.0043 0.0070 0.0279 0.5252 0 DiBP 0.0003 0.0233 0.0362 0.1521 0.9279 0 <0.0001 0.0023 0.0036 0.0152 0.0928 0 BBzP <0.0001 <0.0001 <0.0001 0.0004 0.0151 0 <0.0001 <0.0001 <0.0001 0.0009 0.0376 0 DEHP 0.0009 0.0265 0.0405 0.1494 1.9443 3 (0.18) 0.0021 0.06621 0.1014 0.3734 4.8608 21 (1.3) HI 0.0036 0.1150 0.1684 0.5517 5.5422 30 (1.8) 0.0029 0.0779 0.1198 0.4116 4.8848 21 (1.3) Phthalate HQ based on EFSA TDI >1 HQ based on US EPA RfD >1 Minimum 25th 50th 95th Maximum n (%) Minimum 25th 50th 95th Maximum n (%) DEP <0.0001 0.0004 0.0011 0.0175 1.1211 1 (0.06) <0.0001 0.0003 0.0007 0.0110 0.7007 0 DnBP 0.0004 0.0430 0.0702 0.2791 5.2524 14 (0.9) <0.0001 0.0043 0.0070 0.0279 0.5252 0 DiBP 0.0003 0.0233 0.0362 0.1521 0.9279 0 <0.0001 0.0023 0.0036 0.0152 0.0928 0 BBzP <0.0001 <0.0001 <0.0001 0.0004 0.0151 0 <0.0001 <0.0001 <0.0001 0.0009 0.0376 0 DEHP 0.0009 0.0265 0.0405 0.1494 1.9443 3 (0.18) 0.0021 0.06621 0.1014 0.3734 4.8608 21 (1.3) HI 0.0036 0.1150 0.1684 0.5517 5.5422 30 (1.8) 0.0029 0.0779 0.1198 0.4116 4.8848 21 (1.3) What are the main strengths and weaknesses? This birth cohort, the TMICS cohort, is the first to cover a large sample size of study sites in Taiwan’s four major areas (north, central, south and east). Biomarkers of exposure and outcome were measured in a central laboratory, guaranteeing the high quality of data. One major limitation of this study is that we only measured urinary phthalate metabolites based on a one-spot urine sample taken from the third trimester of pregnant mothers. It is possible that this one measurement cannot represent the entire exposure during the entire duration of pregnancy, particularly if there was a wide variability of urinary phthalate metabolites across three trimesters. Since we have stored urine samples from all three trimesters obtained from the entire birth cohort from the southern Taiwan, we can randomly select some study subjects to measure their urine phthalate metabolites to resolve this question. Can I get hold of the data? Where can I find out more? Collaboration in data analysis and publication will be welcomed and should be sent to the corresponding author at e_encourage@yahoo.com. The dataset of certain demographic characteristics, such as maternal age and education levels and child’s sex, during the study will be available in the Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, at [https://envmed.kmu.edu.tw/index.php/en-GB/data-repository/181-cohort-profile-taiwan-maternal-and-infant-cohort-study-tmics-of-phthalate-exposure-and-health-risk-assessment]. TMICS profile in a nutshell TMICS is a nationwide prospective birth cohort study investigating environmental phthalate exposure and its effects on maternal and child health. Between October 2012 and May 2015, 1631 pregnant women in their third trimester from nine hospitals in Taiwan were recurited, administered questionnaires and asked to provide blood samples and urine samples. Follow-up of pregnant women included short questionnaires (at delivery and 2-3 weeks following delivery) and clinical assessment visits of mother and newborn (at delivery). In October 2016, we started to follow up the study children. The TMICS comprises a wide range of environmental pollutant measures, biochemistry measures and genetic and epigenetic information. TMICS has established a repository of biospecimens of these mothers and children for future environmental and health studies. Certain demographic characteristics of the TMICS dataset are available at [https://envmed.kmu.edu.tw/index.php/en-GB/data-repository/181-cohort-profile-taiwan-maternal-and-infant-cohort-study-tmics-of-phthalate-exposure-and-health-risk-assessment]. Funding The TMICS was supported by Ministry of Education, Republic of China (Taiwan), Ministry of Science and Technology (MOST 106-2314-B-214-007- and MOST 106-2314-B-400-014-MY3), the National Science Council (NSC 100-3114-Y-043-005) and a grant from National Health Research Institutes (grant numbers NHRI EH-102-SP-02; EH-103-SP-02). Neither institution played any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgements We thank all members of the research teams, including following list, who participated in the consortium of this TMICS cohort study. Northern area: Drs Yen-An Tsai, Yu-Fang Huang, Kai-Wei Liao from National Yang Ming University, Taipei, Taiwan; Dr Ming-Song Tsai from Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei, Taiwan; Dr Chih-Yao Chen from Division of Obstetrics and High Risk Pregnancy, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Dr Pei-Wei Wang from Department of Pediatrics, Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan; Dr Li-Wei Huang from Department of Obstetrics & Gynecology, Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan. Middle area: Ms Hui-Chun Chen and the obstetricians and paediatricians for subject recruitments, data collections and specimen collections: Dr Ying-Chih Tseng from the Department of Obstetrics and Gynecology, Hsinchu Cathay General Hospital, Hsinchu, Taiwan; Dr Chaw-Liang Chang from the Department of Pediatrics, Hsinchu Cathay General Hospital, Hsinchu, Taiwan; Dr Tsung-Ho Ying from the Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan; Dr Pen-Hua Su from Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan; Dr Kuei-Cheng Hsu from the Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan; Dr Hsiao-Neng Chen and Dr Jian-Wun Cian. from Department of Pediatrics, Changhua Christian Hospital, Changhua, Taiwan. Southern area: Ms Shiang-Shiun Chen, Yun-Shan Tsai, Sheng-Wen Su, Ching-Yi Chen and the obstetricians and paediatricians for subject recruitments, data collections and specimen collections: Dr Fu-Chen Kuo from Department of Gynecology and Obstetrics, E-Da Hospital, Kaohsiung, Taiwan; Dr Chien-Yi Wu from Department of Pediatrics, E-Da Hospital, Kaohsiung, Taiwan; Dr Yung-Hung Chen from Department of Obstetrics and Gynecology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; Dr Chiu-Lin Wang from Department of Obstetrics and Gynecology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; Dr Cheng-Yu Long from Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Dr Chih-Hsing Hung from Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; Dr Wei-Der Lee from Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Ms Chun-Chi Huang from Department of Medicine Laboratory, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan. East area: Dr Yu‐Hsun Chang from Department of Pediatrics, Buddhist Tzu Chi General Hospital, Hualien, Taiwan; Dr Sheng-Po Kao and Dr Yu-Chi Wei from Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan; Dr Anren Hu from Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien, Taiwan. Conflict of interest: None declared. References 1 Wu MT , Wu CF , Wu JR et al. The public health threat of phthalate-tainted foodstuffs in Taiwan: the policies the government implemented and the lessons we learned . Environment Int 2012 ; 44 : 75 – 9 . Google Scholar Crossref Search ADS 2 Wu CF , Chen BH , Shiea J et al. Temporal changes of urinary oxidative metabolites of di(2-ethylhexyl)phthalate after the 2011 phthalate incident in Taiwanese children: findings of a six month follow-up . Environ Sci Technol 2013 ; 47 : 13754 – 62 . Google Scholar Crossref Search ADS PubMed 3 Kuo FC , Su SW , Wu CF et al. 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International Journal of Epidemiology – Oxford University Press
Published: Aug 1, 2018
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