Table S1. Distribution of metals in maternal first trimester red blood cells for participants with all metals measurements and included in at least one of the body size and adiposity analyses (N=999),a as well as comparison with blood cadmium and lead from female National Health and Nutrition Examination Survey (NHANES) participants (1999-2000) (N=4057) and clinical red blood cell reference ranges for healthy individuals.
Metal
Project Viva GM ± SDb
(ng/g)
25th percentile
(ng/g)
50th percentile
(ng/g)
75th percentile
(ng/g)
Minimum (ng/g)
Maximum (ng/g)
%
>LOD
LOD (ng/g)c
NHANES GM (95% CI)b
(μg/L)
Reference Rangeb
(μg/L)
Arsenic 0.78 ± 2.77 0.43 0.84 1.57 0.10 34.10 90% 0.15 -- --
Barium 3.63 ± 2.34 2.04 3.18 6.02 0.29 59.20 99% 0.41 -- --
Cadmium 0.37 ± 2.12 0.27 0.39 0.55 0.04 6.94 95% 0.06 0.42 (0.39-0.46) --
Cesium 2.54 ± 1.42 2.04 2.56 3.21 0.46 10.00 100% 0.06 -- --
Lead 18.13 ± 1.52 13.70 17.90 23.80 4.41 90.80 100% 0.07 13.70 (13.20-14.30) --
Magnesium 40996.89 ± 1.21 36900.00 41000.00 45800.00 7070.00 76600.00 100% 4.15 -- 40000 - 64000
Manganese 16.00 ± 1.60 13.10 16.10 20.40 0.30 42.90 99% 0.42 -- 12-26
Mercury 3.12 ± 2.83 1.69 3.33 6.51 0.21 117.00 97% 0.30 -- --
Selenium 250.30 ± 1.23 222.00 248.00 280.00 39.00 1090.00 100% 1.73 -- 120 - 300
Zinc 10272.99 ± 1.20 9265.00 10400.00 11600.00 2310.00 22200.00 100% 8.74 -- 9000 - 14700
Abbreviations: GM, geometric mean; LOD, limit of detection; SD, standard deviation.
aNo missing values in this subset.
bProject Viva dataset and Reference Ranges = red blood cell metal measurements; NHANES = whole blood metal measurements.
cMetal concentrations below the LOD were assigned the value of LOD/(square root of 2).
Table S2. Distribution of metals in maternal first trimester red blood cells for participants, using complete case (N=348).a
Metal GM ± SDb
(ng/g)
25th percentile (ng/g)
50th percentile (ng/g)
75th percentile
(ng/g) Minimum (ng/g) Maximum (ng/g)
Arsenic 0.78 ± 2.67 0.46 0.84 1.51 0.11 11.30
Barium 3.68 ± 2.35 2.00 3.25 6.03 0.29 36.00
Cadmium 0.35 ± 2.09 0.27 0.38 0.52 0.04 4.06
Cesium 2.57 ± 1.41 2.11 2.61 3.26 1.02 10.00
Lead 18.34 ± 1.50 13.80 18.40 23.80 5.30 78.40
Magnesium 41213.19 ± 1.19 37000.00 40700.00 45700.00 19100.00 76600.00
Manganese 15.66 ± 1.63 12.80 15.60 20.00 0.30 42.90
Mercury 3.18 ± 2.77 1.71 3.28 6.55 0.21 38.20
Selenium 246.60 ± 1.20 218.00 246.00 275.00 111.00 543.00
Zinc 10218.31 ± 1.21 9140.00 10300.00 11500.00 4630.00 22200.00
Abbreviations: GM, geometric mean; SD, standard deviation.
aNo missing values in this subset.
Table S3. Body size and adiposity measurement distributions, mean and standard deviations (SDs), using complete case (N=348).
Outcome Early-childhood Mean (SD) Mid-childhood Mean (SD) Early adolescence Mean (SD)
SS+TR (mm) 16.85 (4.03) 19.54 (9.06) 28.38 (12.78)
Waist circumference (cm) 51.21 (3.33) 59.12 (7.61) 72.53 (10.87)
Body mass index (z-score) 0.77 (0.97) 0.58 (1.15) 0.54 (1.22)
DXA total-fat-mass-index (kg/m2) -- 4.37 (1.80) 6.17 (2.76)
DXA trunk-fat-mass-index (kg/m2) -- 1.47 (0.82) 2.35 (1.32)
Abbreviations: DXA, dual-energy x-ray absorptiometry; SD, standard deviation; SS+TR, sum of skinfold and tricep thicknesses.
Table S4. Sample characteristics of mother-child pairs from the Project Viva cohort, using complete case (N=348).a
Demographic Characteristics N (%) or mean (standard deviation)
Maternal age (years) 32.67 (4.84)
Maternal pre-pregnancy body mass index (kg/m²)
Underweight (<18.5) 10 (2.60)
Normal (18.5 - <25.0) 236 (61.30)
Overweight (25.0 - <30.0) 88 (22.86)
Obese (≥30.0) 51 (13.25)
Maternal race/ethnicity
Asian 16 (4.16)
Black 49 (12.73)
Hispanic 21 (5.45)
More than one race/ethnicity 14 (3.64)
White 285 (74.03)
Maternal education
Less than college 98 (25.45)
College graduate 287 (74.55)
Household income
≤$70,000 per year 127 (32.99)
>$70,000 per year 258 (67.01)
Maternal Smoking
Never 282 (73.25)
Former 72 (18.70)
During pregnancy 31 (8.05)
Parity
Nulliparous 192 (49.87)
One or more 193 (50.13)
Child Sex
Male 182 (47.27)
Female 203 (52.73)
Child age (years)
Early-childhood visit 3.21 (0.23)
Mid-childhood visit 7.70 (0.62)
Early adolescence visit 12.92 (0.62)
aData was complete for all participants.
Child
Sex Metala
Difference in DXA total fat mass index (kg/m2) [β (95% bootstrap CI)]
Difference in DXA trunk fat mass index (kg/m2) [β (95% bootstrap CI)]
Difference in sum ofsubscapular and tricep skinfold thicknesses (mm)
[β (95% bootstrap CI)]
Difference in waist circumference (cm) [β (95% bootstrap CI)]
Difference in body mass index (z-score)
[β (95% bootstrap CI)]
Mid- childhood
Early adolescence
Mid- childhood
Early adolescence
Early- childhood
Mid- childhood
Early adolescence
Early- childhood
Mid- childhood
Early adolescence
Early childhood
Mid- childhood
Early adolescence Male
(N=301) (N=250) (N=301) (N=250) (N=447) (N=383) (N=361) (N=458) (N=385) (N=361) (N=456) (N=382) (N=360)
All metalsb (0.00, 0.26)0.13 0.06
(-0.11, 0.23) 0.14
(-0.02, 0.31) 0.05
(-0.34, 0.44) 0.04
(-0.03, 0.11) 0.10
(-0.01, 0.21) 0.02
(-0.13, 0.16) 0.02
(-0.01, 0.04) 0.04
(-0.00, 0.07) 0.00
(-0.06, 0.06) 0.18
(-0.03, 0.38) 0.34
(0.10, 0.58) 0.23 (-0.09, 0.55) Essential
metalsc (-0.04, 0.09)0.03 -0.12
(-0.20, -0.04) 0.03
(-0.08, 0.14) -0.22
(-0.34, -0.10) 0.00
(-0.01, 0.01) -0.00
(-0.02, 0.02) -0.03
(-0.05, -0.02) 0.00
(-0.00, 0.00) -0.00
(-0.00, 0.00) -0.01
(-0.01, -0.002) 0.09
(-0.04, 0.22) -0.02
(-0.18, 0.15) -0.27 (-0.48, -0.06) Nonessential
metalsd (-0.02, 0.17)0.07 0.14
(0.05, 0.23) 0.12
(-0.04, 0.28) 0.27
(0.08, 0.46) 0.02
(-0.00, 0.04) 0.04
(0.01, 0.08) 0.04
(0.00, 0.09) 0.00
(-0.00, 0.01) 0.01
(0.00, 0.02) 0.01
(-0.00, 0.03) 0.10
(-0.09, 0.29) 0.37
(0.14, 0.60) 0.45 (0.14, 0.76) Female
(N=298) (N=261) (N=298) (N=261) (N=405) (N=363) (N=354) (N=402) (N=362) (N=356) (N=419) (N=363) (N=356)
All metalsb (-0.06, 0.16)0.05 -0.06
(-0.20, 0.08) 0.07
(-0.06, 0.22) -0.15
(-0.47, 0.17) 0.02
(-0.05, 0.09) 0.01
(-0.10, 0.12) -0.13
(-0.28, 0.03) 0.00
(-0.0, 0.02) 0.01
(-0.02, 0.05) -0.01
(-0.06, 0.03) -0.05
(-0.24, 0.14) 0.10
(-0.12, 0.32) -0.10 (-0.43, 0.22) Essential
metalsc (-0.10, 0.07)-0.01 -0.03
(-0.08, 0.03) -0.01
(-0.11, 0.10) -0.05
(-0.15, 0.06) -0.00
(-0.01, 0.01) -0.01
(-0.02, 0.01) -0.01
(-0.03, 0.01) -0.00
(-0.00, 0.00) -0.00
(-0.00, 0.00) -0.00
(-0.01, 0.00) -0.12
(-0.26, 0.02) -0.03
(-0.20, 0.14) -0.17 (-0.38, 0.04) Nonessential
metalsd (-0.02, 0.12)0.05 0.00
(-0.06, 0.07) 0.10
(-0.02, 0.22) -0.01
(-0.15, 0.13) 0.01
(-0.01, 0.03) 0.01
(-0.03, 0.04) -0.02
(-0.06, 0.02) 0.00
(-0.00, 0.01) 0.01
(-0.00, 0.01) 0.00
(-0.01, 0.01) 0.07
(-0.10, 0.25) 0.14
(-0.07, 0.35) 0.10 (-0.18, 0.37)
Table S5. Quantile g-computation estimates for difference in each outcome for one quartile increase in metal mixtures, stratified by child sex.
Abbreviations: CI, confidence interval; DXA, dual-energy x-ray absorptiometry.
aMetals were log2-transformed in the analyses.
bQuantile g-computation model assessed difference in each outcome for one quartile increase in all metals (arsenic, barium, cadmium, cesium, lead, magnesium, manganese, mercury, selenium, zinc), conditional on the covariates maternal age, pre-pregnancy body mass index, race/ethnicity, education, household income, smoking status, and parity.
cQuantile g-computation model assessed difference in each outcome for one quartile increase in essential metals (magnesium, manganese, selenium, zinc), conditional on the covariates maternal age, pre- pregnancy body mass index, race/ethnicity, education, household income, smoking status, parity, and the nonessential metals.
dQuantile g-computation model assessed difference in each outcome for one quartile increase in nonessential metals (arsenic, barium, cadmium, cesium, lead, mercury), conditional on the covariates maternal age, pre-pregnancy body mass index, race/ethnicity, education, household income, smoking status, parity, and the essential metals.
Metala
Difference in DXA total-fat- mass-index (kg/m2)
[β (95% CI)]
Difference in DXA trunk- fat-mass-index (kg/m2)
[β (95% CI)]
Difference in sum of subscapular and tricep skinfold thicknesses (mm)
[β (95% CI)]
Difference in waist circumference (cm)
[β (95% CI)]
Difference in body mass index (z-score)
[β (95% CI)]
Mid-childhood (N=599)b
Early adolescence
(N=511)b
Mid- childhood
(N=599)b
Early adolescence
(N=511)b
Early childhood
(N=859)b
Mid- childhood
(N=747)b
Early adolescence
(N=715)b
Early childhood
(N=882)b
Mid-childhood (N=748)b
Early adolescence
(N=717)b
Early childhood
(N=875)b
Mid-childhood (N=745)b
Early adolescence
(N=716)b
Arsenic -0.02
(-0.13, 0.09)
-0.08 (-0.25, 0.10)
-0.01 (-0.06, 0.04)
-0.04 (-0.12, 0.04)
0.08 (-0.12, 0.28)
0.05 (-0.43, 0.52)
-0.27 (-0.91, 0.38)
0.00 (-0.18, 0.17)
0.16 (-0.25, 0.58)
-0.26 (-0.83, 0.32)
-0.01 (-0.05, 0.04)
0.03 (-0.03, 0.08)
-0.03 (-0.09, 0.03)
Barium 0.00
(-0.12, 0.12)
-0.10 (-0.29, 0.09)
0.00 (-0.05, 0.06)
-0.04 (-0.14, 0.05)
0.06 (-0.18, 0.29)
-0.05 (-0.60, 0.50)
-0.07 (-0.82, 0.67)
-0.03 (-0.23, 0.17)
0.00 (-0.48, 0.48)
0.10 (-0.56, 0.76)
0.00 (-0.05, 0.05)
0.02 (-0.05, 0.08)
0.04 (-0.03, 0.10)
Cadmium 0.01
(-0.13, 0.15)
0.25 (0.02, 0.48)
0.01 (-0.06, 0.07)
0.12 (0.01, 0.23)
0.30 (0.02, 0.58)
0.09 (-0.55, 0.73)
0.44 (-0.45, 1.33)
0.22 (-0.02, 0.46)
0.24 (-0.32, 0.80)
0.34 (-0.45, 1.13)
0.00 (-0.06, 0.06)
0.01 (-0.07, 0.08)
0.03 (-0.05, 0.11)
Cesium 0.28
(-0.03, 0.59)
0.47 (-0.03, 0.97)
0.12 (-0.02, 0.27)
0.23 (0.00, 0.47)
0.01 (-0.59, 0.61)
0.65 (-0.74, 2.04)
1.25 (-0.63, 3.12)
0.19 (-0.32, 0.71)
0.92 (-0.30, 2.13)
0.41 (-1.25, 2.08)
0.09 (-0.05, 0.22)
0.18 (0.02, 0.35)
0.08 (-0.09, 0.25)
Lead 0.24
(-0.02, 0.50)
0.07 (-0.35, 0.49)
0.11 (0.00, 0.23)
0.06 (-0.14, 0.26)
0.06 (-0.43, 0.54)
0.31 (-0.85, 1.46)
-0.59 (-2.17, 1.00)
0.18 (-0.23, 0.60)
0.41 (-0.61, 1.42)
0.38 (-1.03, 1.79)
0.07 (-0.04, 0.18)
0.07 (-0.07, 0.20)
0.03 (-0.11, 0.18)
Magnesium 0.36
(-0.16, 0.88)
-0.29 (-1.15, 0.56)
0.16 (-0.08, 0.39)
-0.12 (-0.52, 0.29)
-0.16 (-1.25, 0.92)
0.39 (-1.97, 2.76)
-1.41 (-4.67, 1.85)
0.15 (-0.77, 1.06)
0.52 (-1.56, 2.59)
-2.80 (-5.70, 0.09)
0.11 (-0.14, 0.35)
0.08 (-0.20, 0.36)
-0.24 (-0.53, 0.06)
Manganese -0.05
(-0.27, 0.17)
-0.09 (-0.45, 0.27)
-0.04 (-0.14, 0.06)
-0.06 (-0.24, 0.11)
-0.36 (-0.76, 0.04)
-0.78 (-1.76, 0.20)
-0.96 (-2.28, 0.37)
-0.11 (-0.46, 0.23)
-0.39 (-1.25, 0.47)
-0.03 (-1.20, 1.15)
-0.08 (-0.17, 0.01)
-0.04 (-0.16, 0.07)
-0.08 (-0.20, 0.04)
Mercury 0.01
(-0.10, 0.11)
0.04 (-0.13, 0.21)
0.00 (-0.04, 0.05)
0.01 (-0.07, 0.09)
-0.02 (-0.22, 0.18)
0.04 (-0.43, 0.52)
-0.25 (-0.89, 0.39)
-0.01 (-0.18, 0.16)
0.23 (-0.19, 0.65)
-0.14 (-0.70, 0.43)
0.00 (-0.05, 0.04)
0.05 (-0.01, 0.11)
0.02 (-0.04, 0.07)
Selenium -0.15
(-0.65, 0.35)
-0.50 (-1.32, 0.32)
-0.06 (-0.29, 0.17)
-0.25 (-0.64, 0.14)
-0.52 (-1.52, 0.48)
-0.42 (-2.59, 1.75)
-0.11 (-3.06, 2.83)
-0.15 (-1.00, 0.70)
-0.39 (-2.30, 1.51)
-1.69 (-4.30, 0.93)
-0.02 (-0.25, 0.20)
-0.10 (-0.36, 0.16)
-0.22 (-0.49, 0.05)
Zinc -0.04
(-0.58, 0.49)
-0.54 (-1.40, 0.31)
-0.01 (-0.25, 0.23)
-0.23 (-0.63, 0.18)
0.09 (-1.02, 1.20)
-0.46 (-2.91, 1.98)
-1.51 (-4.85, 1.83)
0.79 (-0.15, 1.73)
0.20 (-1.94, 2.34)
-1.90 (-4.86, 1.06)
0.15 (-0.10, 0.41)
-0.04 (-0.33, 0.25)
-0.24 (-0.54, 0.06) Table S6. Multivariate linear regression estimates for association between first trimester red blood cell concentrations of each metal individually and each outcome, conditional on the covariates.
Abbreviations: CI, confidence interval; DXA, dual-energy x-ray absorptiometry.
aMetals were log2-transformed in the analyses.
bLinear regression models were adjusted for maternal age, pre-pregnancy body mass index, race/ethnicity, education, household income, smoking status, parity, and child sex.
Table S7. Multivariate linear regression for association between first trimester red blood cell concentrations of each metal individually and each outcome, stratified by child sex, if cross-product term in multivariable linear regression models with a multiplicative term was p-value <0.05.
Abbreviations:
Ba, barium;
Cd, body mass index, BMI;
cadmium; CI, confidence interval; DXA, dual-energy x- ray
absorptiometry; Hg, mercury; Mg, magnesium; SS+TR, sum of subscapular and tricep skinfold thicknesses; Zn, zinc.
aResults reported when p<0.05 for interaction.
bLinear regression models were adjusted for maternal age, pre-pregnancy body mass index, race/ethnicity, education, household income, smoking status, and parity.
Visit Metal-outcome associationa Assigned female at birth
[β (95% CI)]b
Assigned male at birth [β (95% CI)]b
Early childhood Mg and BMI (z-score) -0.20 (-0.55, 0.16) 0.35 (0.02, 0.69)
Mid-childhood Ba and BMI (z-score) -0.05 (-0.14, 0.04) 0.09 (-0.01, 0.19)
Zn and DXA total-fat-mass-index (kg/m2) -0.81 (-1.58,-0.05) 0.69 (-0.07, 1.45) Zn and DXA trunk-fat-mass-index (kg/m2) -0.32 (-0.67, 0.03) 0.29 (-0.05, 0.64)
Early adolescence
Cd and DXA total-fat-mass-index (kg/m2) -0.12 (-0.41, 0.16) 0.67 (0.31, 1.03) Cd and DXA trunk-fat-mass-index (kg/m2) -0.05 (-0.19, 0.09) 0.32 (0.16, 0.49)
Cd and SS+TR (mm) -0.60 (-1.80, 0.59) 1.63 (0.31, 2.95)
Cd and BMI (z-score) -0.05 (-0.16, 0.06) 0.13 (0.01, 0.25)
Hg andSS+TR (mm) -0.70 (-1.58, 0.18) 0.26 (-0.65, 1.18)
Hg and waist circumference (cm) -0.40 (-1.12, 0.33) 0.20 (-0.66, 1.07) Hg and BMI (z-score) -0.02 (-0.10, 0.06) 0.06 (-0.02, 0.15)
Figure S1. Exclusion criteria for mother-infant pairs in Project Viva included in the analyses.
4,102 pregnant participants
2,670 participants recruited at <22 weeks of gestation
2,341 participants remained eligible
[115 persons moved away from study area, 19 multiple gestations, 195 stillbirths or miscarriages]
2,128 live births
[11 lost to follow-up, 195 withdrew, 7 not specified]
2,100 unique participants included in present analyses [kept first live birth only, for mothers with more than one live birth]
1,390 participants with all 1st trimester metals measured in red blood cells [no mercury measurement for 17 participants]
999 maternal-infant IDs with at least one body size and adiposity measure
Figure S2. Spearman correlation coefficients among adiposity and body size outcome measurements (N=385).
Figure S3. Differences and 95% bootstrap confidence intervals, estimated with quantile g-computation, for body mass index (BMI; z-score), sum of skinfold and tricep thicknesses (SS+TR; mm), waist circumference (WC; cm), DXA total-fat-mass-index (total fat; kg/m2), and DXA trunk-fat-mass- index (trunk fat; kg/m2) for a one quartile increase in (A) nonessential metals (arsenic, barium, cadmium, cesium, lead, mercury), conditional on covariates (maternal age, pre-pregnancy BMI, race/ethnicity, education, household income, smoking, parity, infant sex) and essential metals, and (B) essential metals (magnesium, manganese, selenium, zinc), conditional on covariates and nonessential metals, using complete case (N=348).
(B) Essential Metals (A) Nonessential Metals
Figure S4. Weights representing the proportion of the positive and negative partial associations for each metal in quantile g-computation models examining associations between the essential metal mixture with (A) DXA total fat mass index (kg/m2), (B) DXA trunk fat mass (kg/m2), (C) sum of skinfold thicknesses (mm), (D) waist circumference (cm), and (E) body mass index (z-score) in early adolescence. Metals are ordered by magnitude of weights. Abbreviations: Mg, magnesium; Mn, Manganese; Se, selenium; Zn, zinc. This figure corresponds to the essential metals row of Table 3.
B A
E C D
A B C
Figure S5. Weights representing the proportion
of the positive and negative partial associations for each metal in quantile g-computation
models examining associations between the nonessential metal mixture with (A) DXA total fat mass index (kg/m2) in mid-childhood, (B) DXA total fat mass index (kg/m2) in early adolescence, (C) DXA trunk fat mass (kg/m2) in mid-childhood, (D) waist circumference (cm) in mid-childhood, (E) body mass index (z-score) in mid-childhood, and (F) body mass index (z-score) in early adolescence. Metals are ordered by magnitude of weights.
Abbreviations: As, arsenic; Ba, barium; Cd, cadmium; Cs, cesium; Hg, mercury; Pb, lead. This figure corresponds to the nonessential metals row of Table 3.
