ED-CORTISOL-CBCL

Main results

Author

M. Rolland

Published

November 6, 2024

Note:

1 Main results

1.1 Flowchart

Figure 1: Study flowchart

1.2 Population description

Table 1: Population Description Stratified by Cohort
Characteristic Overall
N = 1,0241		 BiSC
N = 6071		 SEPAGES
N = 4171		 p-value2
Maternal BMI (kg/m2)


<0.001
    Normal (18.5 to 24.9) 687 (71%) 375 (67%) 312 (75%)
    Underweight (<18.5) 48 (4.9%) 20 (3.6%) 28 (6.8%)
    Overweight (>=25) 238 (24%) 164 (29%) 74 (18%)
    Missing 51 48 3
Maternal age (years) 33.9 (31.0, 36.8) 35.0 (32.0, 38.0) 32.3 (30.0, 35.3) <0.001
Maternal education


<0.001
    Below university 156 (15%) 134 (22%) 22 (5.3%)
    University, below master 323 (32%) 168 (28%) 155 (37%)
    University, master or above 543 (53%) 305 (50%) 238 (57%)
    Missing 2 0 2
Ethnicity


<0.001
    European 894 (88%) 495 (82%) 399 (97%)
    Other 126 (12%) 112 (18%) 14 (3.4%)
    Missing 4 0 4
Anxiety z-score 0.00 (-0.70, 0.60) -0.18 (-0.70, 0.55) 0.00 (-0.70, 0.60) 0.9
    Missing 80 67 13
Parity


<0.001
    Nulliparous 587 (57%) 393 (65%) 194 (47%)
    Multiparous 437 (43%) 214 (35%) 223 (53%)
Passive smoking during pregnancy 305 (31%) 229 (39%) 76 (19%) <0.001
    Missing 45 21 24
Alcohol intake during pregnancy 262 (27%) 169 (29%) 93 (23%) 0.014
    Missing 38 34 4
Folic acid intake during pregnancy 705 (82%) 338 (76%) 367 (88%) <0.001
    Missing 163 161 2
Active smoking during pregnancy 68 (6.9%) 45 (7.5%) 23 (6.0%) 0.4
    Missing 44 8 36
Timing of second trimester urine sample (gest. weeks) 18.9 (17.4, 20.9) 20.3 (18.4, 22.6) 17.7 (16.4, 18.9) <0.001
    Missing 172 135 37
Timing of third trimester urine sample (gest. weeks) 35.70 (34.35, 37.00) 36.71 (35.71, 37.71) 34.00 (32.30, 35.30) <0.001
    Missing 112 70 42
Hair collection (gest. weeks) 33.0 (31.7, 41.9) 31.9 (31.1, 32.4) 42.0 (41.1, 42.9) <0.001
    Missing 98 98 0
Time between hair coll. and horm. assessment (months) 12 (5, 49) 6 (4, 11) 51 (45, 59) <0.001
    Missing 155 98 57
∑Cortisol (nmol/g) 0.024 (0.016, 0.037) 0.027 (0.020, 0.037) 0.019 (0.010, 0.037) <0.001
    Missing 171 102 69
Season of birth


0.5
    Winter 202 (20%) 116 (19%) 86 (21%)
    Other 822 (80%) 491 (81%) 331 (79%)
Child sex


0.075
    Male 528 (52%) 299 (49%) 229 (55%)
    Female 496 (48%) 308 (51%) 188 (45%)
Breasfeeding (N weeks) 35 (17, 48) 48 (26, 48) 26 (15, 42) <0.001
    Missing 18 9 9
Child in daycare at 12 months 378 (45%) 255 (51%) 123 (35%) <0.001
    Missing 175 111 64
Age at CBCL questionnaire (months) 19.72 (18.74, 24.55) 18.84 (18.44, 19.44) 24.68 (24.45, 25.12) <0.001
Externalizing problems 11 (7, 16) 10 (5, 14) 12 (9, 17) <0.001
    Missing 1 0 1
Internalizing problems 4.0 (2.0, 8.0) 3.0 (1.0, 6.0) 6.0 (3.0, 9.0) <0.001
1 n (%); Median (Q1, Q3)
2 Pearson’s Chi-squared test; Wilcoxon rank sum test

1.3 Exposure description

Table 2: Exposure Detection Rates and Description Stratified by Cohort and by Pool
Raw data
Standardized data
BiSC
SEPAGES
BiSC
SEPAGES
N %>LOD p5 p50 p95 N %>LOD p5 p50 p95 N %>LOD p5 p50 p95 N %>LOD p5 p50 p95
Trimester 2
Benzophenone-3 455 100% 0.91 5.18 140.43 415 100% 0.25 1.14 37.35 455 100% 0.68 3.54 81.91 415 100% 0.17 0.81 26.13
Bisphenol A 455 86% 0.03 2.52 25.22 415 99% 0.67 2.00 7.97 455 86% 0.02 1.00 11.53 415 100% 0.65 1.83 7.93
Bisphenol S 455 59% 0.03 0.50 3.55 415 24% 0.00 0.00 3.69 455 61% 0.03 0.33 2.83 415 13% 0.00 0.00 1.01
Ethylparaben 455 100% 0.85 2.53 48.86 415 100% 0.26 0.70 30.09 455 100% 0.90 2.20 40.21 415 100% 0.29 0.87 35.45
Methylparaben 455 100% 4.48 14.91 231.49 415 100% 2.68 12.33 280.62 455 100% 7.08 19.98 313.08 415 100% 2.15 10.77 212.00
Propylparaben 455 87% 0.02 0.52 37.27 415 80% 0.01 0.40 59.34 455 87% 0.02 0.52 37.27 415 78% 0.00 0.32 42.51
Triclosan 455 93% 0.04 0.79 126.12 415 98% 0.21 0.91 186.31 455 94% 0.03 0.59 88.67 415 98% 0.21 0.91 186.31
Trimester 3
Benzophenone-3 523 100% 0.82 4.89 128.64 409 100% 0.24 0.99 27.55 523 100% 0.51 3.39 71.23 409 100% 0.17 0.71 16.77
Bisphenol A 523 87% 0.03 2.90 25.39 409 98% 0.52 1.78 9.20 523 87% 0.02 1.16 10.46 409 99% 0.49 1.66 7.83
Bisphenol S 523 56% 0.03 0.43 3.30 407 27% 0.00 0.00 2.94 523 58% 0.02 0.30 2.76 407 11% 0.00 0.00 0.32
Ethylparaben 523 100% 0.93 2.70 30.83 409 100% 0.21 0.73 21.85 523 100% 0.98 2.54 23.86 409 100% 0.25 0.91 25.45
Methylparaben 523 100% 5.16 17.63 1,160.68 409 100% 2.86 12.24 2,635.94 523 100% 7.79 24.55 1,321.53 409 100% 2.10 11.06 1,993.47
Propylparaben 523 89% 0.02 0.69 149.33 409 80% 0.00 0.56 158.91 523 89% 0.02 0.69 149.33 409 77% 0.00 0.38 110.42
Triclosan 523 89% 0.02 0.71 110.14 409 98% 0.19 0.86 197.39 523 90% 0.02 0.50 61.85 409 98% 0.19 0.86 197.39

1.4 EWAS

See Table 4 for detail on model Ns.

1.4.1 Direct association

Figure 2: Adjusted estimates and CIs from EWAS for internalising and externalising CBCL VS pregnancy exposure
Figure 3: Adjusted estimates and CIs for externalising and internalising CBCL, stratified by cohort for associations that were significant in the overall EWAS
Figure 4: Adjusted estimates and CIs from EWAS for internalising and externalising CBCL VS pregnancy exposure, complete case analysis
Figure 5: Adjusted estimates and CIs from EWAS for internalising and externalising CBCL VS pregnancy exposure, using unstandardised exposure data
Figure 6: Adjusted estimates and CIs from EWAS for internalising and externalising CBCL VS pregnancy exposure, without top and bottom 1%

1.4.1.1 Non linear (quartiles)

see allp-values Table 5

Figure 7: Adjusted estimates and CIs for BPA and PRPA coded as quartiles and for Pool 2 only (as determined in ADD REF)

1.4.2 Sex interaction

Figure 8: Adjusted estimates and CIs for compound/score couples that showed signs of interaction with sex (p < 0.1)
Figure 9: Adjusted estimates and CIs for compound/score couples that showed signs of interaction with sex (p < 0.1)
Figure 10: Adjusted estimates and CIs for compound/score couples that showed signs of interaction with sex (p < 0.1), complete case data
Figure 11: Adjusted estimates and CIs for compound/score couples that showed signs of interaction with sex (p < 0.1), on not standardised exposure data
Figure 12: Adjusted estimates and CIs for compound/score couples that showed signs of interaction with sex (p < 0.1), without top and bottom 1%

2 BKMR

2.1 Overall

Figure 13: Overall risk (did not include BPS and BUPA)

2.2 By sex

Figure 14: Overall risk (did not include BPS and BUPA), by sex

3 Mediation

Nonparametric Bootstrap Confidence Intervals with the Percentile Method

3.1 Main and by sex

Table 3: Adjusted estimates and CIs for Direct and Indirect effect of mediation analysis
Male + Female
Female
Female
Male
Est. (95% CI) p
Est. (95% CI) p Est. (95% CI) p
Methylparaben - Trimester 3 - Internalizing
Indirect effect 0.000 (-0.001, 0.002) 0.9 — — — —
Direct effect 0.051 (0.013, 0.085) 0.006 — — — —
Total Effect 0.051 (0.013, 0.085) 0.006 — — — —
Prop. Mediated 0.003 (-0.041, 0.064) 0.9 — — — —
Methylparaben - Trimester 3 - Externalizing
Indirect effect 0.000 (-0.002, 0.002) >0.9 — — — —
Direct effect 0.048 (0.011, 0.087) 0.002 — — — —
Total Effect 0.048 (0.010, 0.087) 0.002 — — — —
Prop. Mediated 0.000 (-0.052, 0.037) >0.9 — — — —
Propylparaben - Trimester 2 - Externalizing
Indirect effect — — — — -0.002 (-0.008, 0.004) 0.5
Direct effect — — — — -0.033 (-0.073, 0.008) 0.12
Total Effect — — — — -0.035 (-0.074, 0.005) 0.10
Prop. Mediated — — — — 0.044 (-0.417, 0.704) 0.6
Butylparaben - Trimester 2 - Internalizing
Indirect effect — — — — -0.011 (-0.055, 0.013) 0.4
Direct effect — — — — -0.275 (-0.542, -0.033) 0.034
Total Effect — — — — -0.286 (-0.561, -0.038) 0.030
Prop. Mediated — — — — 0.039 (-0.073, 0.265) 0.4
Bisphenol S - Trimester 3 - Internalizing
Indirect effect — — 0.000 (-0.017, 0.012) >0.9 — —
Direct effect — — 0.232 (0.057, 0.425) 0.016 — —
Total Effect — — 0.232 (0.059, 0.425) 0.016 — —
Prop. Mediated — — 0.000 (-0.089, 0.080) >0.9 — —

4 Supplementary data

4.1 N for each model

Table 4: Final N by pool and combination type and by cohort
Characteristic Overall
N = 1,0241		 BiSC
N = 6071		 SEPAGES
N = 4171
pool1 870 (85%) 455 (75%) 415 (100%)
pool2 932 (91%) 523 (86%) 409 (98%)
1 n (%)

4.2 Non linearity test

Table 5: Non linearity test
Internalizing
Externalizing
Anova Trend Coding Anova Trend Coding
Trimester 2
Benzophenone-3 0.044 0.036 Linear 0.10 — Linear
Bisphenol A 0.4 — Linear 0.4 — Linear
Ethylparaben 0.3 — Linear 0.3 — Linear
Methylparaben 0.002 0.037 Linear 0.002 0.013 Linear
Propylparaben 0.4 — Linear 0.5 — Linear
Triclosan 0.080 — Linear 0.10 — Linear
Trimester 3
Benzophenone-3 0.005 <0.001 Linear 0.8 — Linear
Bisphenol A 0.024 0.3 Quartiles 0.2 — Linear
Ethylparaben 0.044 0.008 Linear 0.7 — Linear
Methylparaben <0.001 0.4 Quartiles 0.3 — Linear
Propylparaben 0.015 0.5 Quartiles 0.2 — Linear
Triclosan 0.046 0.3 Quartiles 0.011 0.060 Quartiles

4.3 Model outputs

4.3.1 EWAS

4.3.1.1 Main

Table 6: Adjusted Estimates and Confidence Intervals from EWAS for Internalising and Externalising CBCL Scores vs. Pregnancy Exposure
Externalizing
Internalizing
N Estimate (95% CI) p N Estimate (95% CI) p
Trimester 2
Benzophenone-3 869.00 0.03 (-0.08, 0.13) 0.6 870.00 0.01 (-0.09, 0.11) 0.8
Bisphenol A 869.00 -0.05 (-0.16, 0.05) 0.3 870.00 -0.07 (-0.18, 0.04) 0.2
Bisphenol S 869.00 -0.12 (-0.26, 0.03) 0.11 870.00 -0.06 (-0.2, 0.08) 0.4
Butylparaben 869.00 -0.11 (-0.28, 0.06) 0.2 870.00 -0.06 (-0.23, 0.11) 0.5
Ethylparaben 869.00 -0.07 (-0.19, 0.05) 0.3 870.00 0 (-0.12, 0.11) >0.9
Methylparaben 869.00 -0.1 (-0.22, 0.02) 0.088 870.00 -0.04 (-0.16, 0.07) 0.4
Propylparaben 869.00 -0.05 (-0.11, 0.01) 0.12 870.00 -0.04 (-0.09, 0.02) 0.2
Triclosan 869.00 0.07 (0, 0.15) 0.065 870.00 0.02 (-0.06, 0.09) 0.6
Trimester 3
Benzophenone-3 931.00 0.06 (-0.03, 0.16) 0.2 932.00 -0.08 (-0.18, 0.02) 0.11
Bisphenol A 931.00 0 (-0.1, 0.09) >0.9 932.00 -0.02 (-0.12, 0.07) 0.6
Bisphenol S 931.00 0.04 (-0.1, 0.17) 0.6 932.00 0.05 (-0.08, 0.19) 0.4
Butylparaben 931.00 0.07 (-0.1, 0.24) 0.4 932.00 -0.01 (-0.18, 0.16) >0.9
Ethylparaben 931.00 0.05 (-0.07, 0.17) 0.4 932.00 -0.06 (-0.18, 0.06) 0.3
Methylparaben 931.00 0.1 (0.02, 0.18) 0.017 932.00 0.11 (0.03, 0.19) 0.010
Propylparaben 931.00 0.03 (-0.02, 0.08) 0.3 932.00 0.02 (-0.03, 0.07) 0.5
Triclosan 931.00 0.05 (-0.02, 0.12) 0.15 932.00 0 (-0.07, 0.07) >0.9
Table 7: Adjusted Estimates and Confidence Intervals from EWAS for Internalising and Externalising CBCL Scores vs. Pregnancy Exposure
Externalizing
Internalizing
N Estimate (95% CI) p N Estimate (95% CI) p
Trimester 2
Benzophenone-3 869.00 0.17 (-0.51, 0.87) 0.6 870.00 0.05 (-0.35, 0.47) 0.8
Bisphenol A 869.00 -0.35 (-1.03, 0.36) 0.3 870.00 -0.28 (-0.68, 0.14) 0.2
Bisphenol S 869.00 -0.77 (-1.67, 0.17) 0.11 870.00 -0.24 (-0.77, 0.34) 0.4
Butylparaben 869.00 -0.74 (-1.81, 0.39) 0.2 870.00 -0.25 (-0.88, 0.44) 0.5
Ethylparaben 869.00 -0.45 (-1.2, 0.33) 0.3 870.00 -0.02 (-0.47, 0.46) >0.9
Methylparaben 869.00 -0.67 (-1.41, 0.1) 0.088 870.00 -0.18 (-0.62, 0.29) 0.4
Propylparaben 869.00 -0.31 (-0.7, 0.08) 0.12 870.00 -0.14 (-0.37, 0.09) 0.2
Triclosan 869.00 0.48 (-0.03, 1.01) 0.065 870.00 0.07 (-0.23, 0.39) 0.6
Trimester 3
Benzophenone-3 931.00 0.43 (-0.22, 1.1) 0.2 932.00 -0.31 (-0.68, 0.07) 0.11
Bisphenol A 931.00 -0.01 (-0.63, 0.63) >0.9 932.00 -0.1 (-0.46, 0.28) 0.6
Bisphenol S 931.00 0.25 (-0.63, 1.15) 0.6 932.00 0.22 (-0.31, 0.78) 0.4
Butylparaben 931.00 0.48 (-0.64, 1.65) 0.4 932.00 -0.04 (-0.68, 0.66) >0.9
Ethylparaben 931.00 0.36 (-0.44, 1.18) 0.4 932.00 -0.23 (-0.68, 0.24) 0.3
Methylparaben 931.00 0.67 (0.12, 1.24) 0.017 932.00 0.44 (0.1, 0.8) 0.010
Propylparaben 931.00 0.2 (-0.14, 0.53) 0.3 932.00 0.06 (-0.14, 0.27) 0.5
Triclosan 931.00 0.35 (-0.12, 0.83) 0.15 932.00 0.01 (-0.26, 0.3) >0.9

4.3.1.2 Non linear

Table 8: Non linear models
Externalizing
Internalizing
N Estimate (95% CI) p N Estimate (95% CI) p
Trimester 3
Bisphenol A — — — 932.00 -0.1 (-0.29, 0.09) 0.3
Bisphenol A — — — 932.00 -0.06 (-0.25, 0.13) 0.5
Bisphenol A — — — 932.00 -0.11 (-0.3, 0.08) 0.2
Methylparaben — — — 932.00 0.04 (-0.14, 0.23) 0.6
Methylparaben — — — 932.00 0.11 (-0.08, 0.3) 0.3
Methylparaben — — — 932.00 0.19 (0, 0.37) 0.047
Propylparaben — — — 932.00 -0.09 (-0.27, 0.09) 0.3
Propylparaben — — — 932.00 -0.17 (-0.35, 0.01) 0.066
Propylparaben — — — 932.00 0.06 (-0.12, 0.24) 0.5
Triclosan 931.00 -0.15 (-0.33, 0.03) 0.10 932.00 -0.22 (-0.4, -0.04) 0.016
Triclosan 931.00 0.06 (-0.13, 0.24) 0.5 932.00 -0.06 (-0.24, 0.13) 0.5
Triclosan 931.00 0.13 (-0.06, 0.31) 0.2 932.00 0.01 (-0.17, 0.2) 0.9

4.3.1.3 Sensitivity: By cohort

Table 9: Adjusted Estimates and Confidence Intervals from EWAS for Internalising and Externalising CBCL Scores vs. Pregnancy Exposure, Stratified by Cohort
cohort
Externalizing
Internalizing
N Estimate (95% CI) p N Estimate (95% CI) p
Trimester 3
Methylparaben BiSC 523.00 0.16 (0.03, 0.29) 0.018 523.00 0.13 (0, 0.26) 0.046
Methylparaben SEPAGES 408.00 0.07 (-0.04, 0.17) 0.2 409.00 0.11 (0.01, 0.22) 0.032

4.3.1.4 Sensitivity: complete case

Table 10: Adjusted Estimates and Confidence Intervals from EWAS for Internalising and Externalising CBCL Scores vs. Pregnancy Exposure, Limited to Complete Cases
Externalizing
Internalizing
N Estimate (95% CI) p N Estimate (95% CI) p
Trimester 2
Benzophenone-3 567.00 0.02 (-0.11, 0.14) 0.8 567.00 0.08 (-0.05, 0.2) 0.2
Bisphenol A 567.00 -0.05 (-0.19, 0.09) 0.5 567.00 -0.07 (-0.21, 0.06) 0.3
Bisphenol S 567.00 -0.16 (-0.34, 0.02) 0.089 567.00 -0.05 (-0.23, 0.12) 0.5
Butylparaben 567.00 -0.09 (-0.3, 0.12) 0.4 567.00 0.01 (-0.2, 0.21) >0.9
Ethylparaben 567.00 -0.02 (-0.16, 0.12) 0.8 567.00 0.03 (-0.11, 0.17) 0.7
Methylparaben 567.00 -0.04 (-0.18, 0.1) 0.6 567.00 -0.02 (-0.15, 0.12) 0.8
Propylparaben 567.00 -0.01 (-0.08, 0.05) 0.7 567.00 -0.03 (-0.1, 0.04) 0.4
Triclosan 567.00 0.05 (-0.04, 0.14) 0.3 567.00 0.02 (-0.07, 0.1) 0.7
Trimester 3
Benzophenone-3 581.00 0.08 (-0.05, 0.2) 0.2 581.00 0.02 (-0.1, 0.14) 0.7
Bisphenol A 581.00 -0.04 (-0.16, 0.08) 0.5 581.00 0.04 (-0.08, 0.15) 0.6
Bisphenol S 581.00 0.07 (-0.1, 0.24) 0.4 581.00 0.05 (-0.11, 0.21) 0.5
Butylparaben 581.00 0.26 (0.05, 0.47) 0.016 581.00 0.16 (-0.05, 0.36) 0.13
Ethylparaben 581.00 0.1 (-0.05, 0.26) 0.2 581.00 0.02 (-0.12, 0.17) 0.8
Methylparaben 581.00 0.11 (0.01, 0.21) 0.025 581.00 0.13 (0.04, 0.23) 0.005
Propylparaben 581.00 0.03 (-0.04, 0.09) 0.4 581.00 0.03 (-0.03, 0.09) 0.3
Triclosan 581.00 0.09 (0, 0.18) 0.046 581.00 0.01 (-0.08, 0.1) 0.8

4.3.1.5 Sensitivity: Non standardised

Table 11: Adjusted Estimates and Confidence Intervals from EWAS for Internalising and Externalising CBCL Scores vs. Pregnancy Exposure, Using Non-Standardised Exposures Data
Externalizing
Internalizing
N Estimate (95% CI) p N Estimate (95% CI) p
Trimester 2
Benzophenone-3 869.00 0.02 (-0.08, 0.12) 0.7 870.00 0.02 (-0.08, 0.12) 0.7
Bisphenol A 869.00 -0.04 (-0.14, 0.06) 0.4 870.00 -0.05 (-0.15, 0.05) 0.4
Bisphenol S 869.00 -0.12 (-0.26, 0.03) 0.11 870.00 -0.06 (-0.2, 0.08) 0.4
Butylparaben 869.00 -0.11 (-0.28, 0.06) 0.2 870.00 -0.06 (-0.23, 0.11) 0.5
Ethylparaben 869.00 -0.08 (-0.19, 0.03) 0.2 870.00 -0.01 (-0.12, 0.1) 0.9
Methylparaben 869.00 -0.12 (-0.23, -0.01) 0.039 870.00 -0.04 (-0.16, 0.07) 0.5
Propylparaben 869.00 -0.05 (-0.11, 0.01) 0.11 870.00 -0.03 (-0.09, 0.03) 0.4
Triclosan 869.00 0.07 (-0.01, 0.14) 0.082 870.00 0.02 (-0.06, 0.09) 0.7
Trimester 3
Benzophenone-3 931.00 0.06 (-0.03, 0.16) 0.2 932.00 -0.07 (-0.17, 0.02) 0.13
Bisphenol A 931.00 0 (-0.1, 0.09) >0.9 932.00 -0.01 (-0.11, 0.08) 0.8
Bisphenol S 931.00 0.04 (-0.1, 0.17) 0.6 932.00 0.05 (-0.08, 0.19) 0.4
Butylparaben 931.00 0.07 (-0.1, 0.24) 0.4 932.00 -0.01 (-0.18, 0.16) >0.9
Ethylparaben 931.00 0.04 (-0.07, 0.16) 0.5 932.00 -0.05 (-0.17, 0.06) 0.4
Methylparaben 931.00 0.1 (0.02, 0.18) 0.020 932.00 0.1 (0.02, 0.18) 0.011
Propylparaben 931.00 0.04 (-0.01, 0.09) 0.2 932.00 0.02 (-0.03, 0.07) 0.4
Triclosan 931.00 0.05 (-0.02, 0.12) 0.15 932.00 0 (-0.07, 0.07) >0.9

4.3.1.6 Sensitivity: Winsorised

Table 12: Adjusted Estimates and Confidence Intervals from EWAS for Internalising and Externalising CBCL Scores vs. Pregnancy Exposure, Excluding Top and Bottom 1% of Exposure and Outcome Values
Externalizing
Internalizing
N Estimate (95% CI) p N Estimate (95% CI) p
Trimester 2
Benzophenone-3 869.00 0.03 (-0.08, 0.13) 0.6 870.00 0.02 (-0.08, 0.12) 0.7
Bisphenol A 869.00 -0.05 (-0.16, 0.05) 0.3 870.00 -0.07 (-0.18, 0.03) 0.2
Ethylparaben 869.00 -0.06 (-0.18, 0.06) 0.3 870.00 0 (-0.12, 0.12) >0.9
Methylparaben 869.00 -0.1 (-0.22, 0.02) 0.11 870.00 -0.05 (-0.17, 0.07) 0.4
Propylparaben 869.00 -0.05 (-0.11, 0.01) 0.11 870.00 -0.04 (-0.1, 0.02) 0.2
Triclosan 869.00 0.07 (-0.01, 0.15) 0.069 870.00 0.02 (-0.06, 0.09) 0.7
Trimester 3
Benzophenone-3 931.00 0.06 (-0.04, 0.16) 0.2 932.00 -0.08 (-0.18, 0.02) 0.10
Bisphenol A 931.00 0 (-0.1, 0.09) >0.9 932.00 -0.02 (-0.12, 0.07) 0.6
Ethylparaben 931.00 0.06 (-0.07, 0.18) 0.4 932.00 -0.05 (-0.17, 0.07) 0.4
Methylparaben 931.00 0.1 (0.01, 0.18) 0.023 932.00 0.11 (0.03, 0.19) 0.010
Propylparaben 931.00 0.03 (-0.02, 0.08) 0.3 932.00 0.02 (-0.04, 0.07) 0.6
Triclosan 931.00 0.05 (-0.02, 0.12) 0.2 932.00 0 (-0.07, 0.07) >0.9

4.3.2 Sex interaction

4.3.2.1 Main

Table 13: Adjusted Estimates and Confidence Intervals from EWAS for Internalising and Externalising CBCL Scores stratified by child sex, performed only when the p-value for interaction was less than 0.1
sex
Externalizing
Internalizing
N Estimate (95% CI) p N Estimate (95% CI) p
Trimester 2
Bisphenol A Male 869 0.04 (-0.11, 0.18) 0.6 — —
Bisphenol A Female 869 -0.14 (-0.29, 0) 0.056 — —
Butylparaben Male — — 870 0.11 (-0.12, 0.34) 0.3
Butylparaben Female — — 870 -0.28 (-0.53, -0.03) 0.031
Propylparaben Male 869 0 (-0.08, 0.08) >0.9 — —
Propylparaben Female 869 -0.11 (-0.19, -0.02) 0.016 — —
Trimester 3
Bisphenol S Male 931 0.17 (-0.01, 0.35) 0.068 932 0.22 (0.04, 0.4) 0.018
Bisphenol S Female 931 -0.1 (-0.29, 0.08) 0.3 932 -0.12 (-0.3, 0.07) 0.2
Table 14: Adjusted Estimates and Confidence Intervals from EWAS for Internalising and Externalising CBCL Scores stratified by child sex, performed only when the p-value for interaction was less than 0.1
sex
Externalizing
Internalizing
N Estimate (95% CI) p N Estimate (95% CI) p
Trimester 2
Bisphenol A Male 869 0.24 (-0.71, 1.24) 0.6 — —
Bisphenol A Female 869 -0.93 (-1.84, 0.02) 0.056 — —
Butylparaben Male — — 870 0.45 (-0.46, 1.46) 0.3
Butylparaben Female — — 870 -1.04 (-1.85, -0.1) 0.031
Propylparaben Male 869 0.02 (-0.51, 0.57) >0.9 — —
Propylparaben Female 869 -0.69 (-1.24, -0.13) 0.016 — —
Trimester 3
Bisphenol S Male 931 1.15 (-0.08, 2.44) 0.068 932 0.92 (0.15, 1.76) 0.018
Bisphenol S Female 931 -0.67 (-1.83, 0.56) 0.3 932 -0.46 (-1.12, 0.27) 0.2
Table 15: P-value for the interaction term between exposure and sex (Wald p)
internalizing externalizing
Pool 1
BP3 0.767735466 0.58960083
BPA 0.863409684 0.07854125
ETPA 0.246827217 0.82040447
MEPA 0.230402178 0.51818158
PRPA 0.236573898 0.07027870
TRCS 0.630109467 0.40188028
BPS 0.569090655 0.53045018
BUPA 0.025089195 0.81842980
Pool 2
BP3 0.906144770 0.59321451
BPA 0.503051896 0.40026034
ETPA 0.244169087 0.13012573
MEPA 0.151457612 0.25733801
PRPA 0.227069353 0.76624277
TRCS 0.807314186 0.60875373
BPS 0.009052989 0.03696906
BUPA 0.349205708 0.42446714

4.3.2.2 Sensitivity: Complete case

Table 16: Adjusted estimates and CIs from EWAS for internalising and externalising CBCL VS pregnancy exposure, including sex interaction limited to complete case data
sex
Externalizing
Internalizing
N Estimate (95% CI) p N Estimate (95% CI) p
Trimester 2
Bisphenol A Male 567 0.08 (-0.12, 0.27) 0.4 — —
Bisphenol A Female 567 -0.16 (-0.35, 0.02) 0.088 — —
Butylparaben Male — — 567 0.15 (-0.13, 0.42) 0.3
Butylparaben Female — — 567 -0.17 (-0.47, 0.14) 0.3
Propylparaben Male 567 0.07 (-0.03, 0.16) 0.2 — —
Propylparaben Female 567 -0.11 (-0.21, 0) 0.040 — —
Trimester 3
Bisphenol S Male 581 0.11 (-0.12, 0.34) 0.4 581 0.11 (-0.11, 0.33) 0.3
Bisphenol S Female 581 0.03 (-0.2, 0.26) 0.8 581 -0.01 (-0.23, 0.21) >0.9

4.3.2.3 Sensitivity: Non standardised

Table 17: Adjusted estimates and CIs from EWAS for internalising and externalising CBCL VS pregnancy exposure, using no standardised exposure data
sex
Externalizing
Internalizing
N Estimate (95% CI) p N Estimate (95% CI) p
Trimester 2
Bisphenol A Male 869 0.04 (-0.1, 0.19) 0.6 — —
Bisphenol A Female 869 -0.12 (-0.27, 0.02) 0.089 — —
Butylparaben Male — — 870 0.11 (-0.12, 0.34) 0.3
Butylparaben Female — — 870 -0.28 (-0.53, -0.03) 0.031
Propylparaben Male 869 0.01 (-0.08, 0.09) 0.9 — —
Propylparaben Female 869 -0.11 (-0.19, -0.02) 0.015 — —
Trimester 3
Bisphenol S Male 931 0.17 (-0.01, 0.35) 0.068 932 0.22 (0.04, 0.4) 0.018
Bisphenol S Female 931 -0.1 (-0.29, 0.08) 0.3 932 -0.12 (-0.3, 0.07) 0.2

4.3.2.4 Sensitivity: Winsorised

Table 18: Adjusted estimates and CIs from EWAS for internalising and externalising CBCL VS pregnancy exposure, excludeing top and bottom 1% exposure and outcome values
compound pool sex score n est_ci p
bpa pool1 Male externalizing_sqrt 869 0.03 (-0.11, 0.18) 0.6
bpa pool1 Female externalizing_sqrt 869 -0.15 (-0.29, 0.00) 0.055
prpa pool1 Male externalizing_sqrt 869 0.00 (-0.08, 0.08) >0.9
prpa pool1 Female externalizing_sqrt 869 -0.11 (-0.20, -0.02) 0.017

4.3.2.5 Sensitivity: By cohort

Table 19: Adjusted Estimates and Confidence Intervals from EWAS for Internalising and Externalising CBCL Scores vs. Pregnancy Exposure, Stratified by Cohort and by child sex
sex cohort
Externalizing
Internalizing
N Estimate (95% CI) p N Estimate (95% CI) p
Trimester 2
Bisphenol A Male BiSC 455 0.06 (-0.12, 0.23) 0.5 — —
Bisphenol A Male SEPAGES 414 -0.2 (-0.54, 0.13) 0.2 — —
Bisphenol A Female BiSC 455 -0.19 (-0.37, -0.02) 0.032 — —
Bisphenol A Female SEPAGES 414 0.09 (-0.28, 0.45) 0.6 — —
Butylparaben Male BiSC — — 455 -0.07 (-0.43, 0.28) 0.7
Butylparaben Male SEPAGES — — 415 0.28 (0, 0.57) 0.054
Butylparaben Female BiSC — — 455 -0.18 (-0.59, 0.24) 0.4
Butylparaben Female SEPAGES — — 415 -0.34 (-0.65, -0.03) 0.034
Propylparaben Male BiSC 455 0.02 (-0.12, 0.16) 0.8 — —
Propylparaben Male SEPAGES 414 0.01 (-0.09, 0.11) 0.9 — —
Propylparaben Female BiSC 455 -0.06 (-0.2, 0.07) 0.3 — —
Propylparaben Female SEPAGES 414 -0.16 (-0.27, -0.04) 0.006 — —
Trimester 3
Bisphenol S Male BiSC 523 0.28 (0.02, 0.53) 0.037 523 0.29 (0.03, 0.55) 0.026
Bisphenol S Male SEPAGES 408 0.04 (-0.23, 0.3) 0.8 409 0.15 (-0.11, 0.41) 0.3
Bisphenol S Female BiSC 523 -0.22 (-0.47, 0.02) 0.078 523 -0.16 (-0.4, 0.09) 0.2
Bisphenol S Female SEPAGES 408 0.06 (-0.25, 0.37) 0.7 409 -0.06 (-0.36, 0.25) 0.7

4.3.3 Mediation

4.3.3.1 By cohort

Table 20: Adjusted estimates and CIs for Direct and Indirect effect of mediation analysis, by cohort
Internalizing
Externalizing
N Estimate (95% CI) p N Estimate (95% CI) p
Methylparaben, Trimester 3, BiSC
Indirect effect 463 0.001 (-0.002, 0.007) 0.6 463 0.001 (-0.002, 0.006) 0.6
Direct effect 463 0.066 (0.008, 0.125) 0.024 463 0.069 (0.012, 0.126) 0.024
Total Effect 463 0.068 (0.008, 0.125) 0.022 463 0.070 (0.014, 0.129) 0.024
Prop. Mediated 463 0.018 (-0.048, 0.163) 0.6 463 0.018 (-0.052, 0.159) 0.6
Methylparaben, Trimester 3, SEPAGES
Indirect effect 344 0.002 (-0.003, 0.008) 0.5 343 0.001 (-0.003, 0.006) 0.7
Direct effect 344 0.047 (0.005, 0.095) 0.022 343 0.041 (-0.012, 0.096) 0.13
Total Effect 344 0.049 (0.006, 0.095) 0.018 343 0.042 (-0.010, 0.096) 0.12
Prop. Mediated 344 0.032 (-0.122, 0.248) 0.6 343 0.020 (-0.226, 0.297) 0.8

4.3.3.2 By sex and by cohort

Table 21: Adjusted estimates and CIs for Direct and Indirect effect of mediation analysis, by cohort and by sex
Internalizing
Externalizing
N Estimate (95% CI) p N Estimate (95% CI) p
Bisphenol S, Trimester 3, Male, BiSC
Indirect effect 214 -0.006 (-0.041, 0.022) 0.7 — — —
Direct effect 214 0.305 (0.020, 0.565) 0.030 — — —
Total Effect 214 0.299 (0.019, 0.559) 0.030 — — —
Prop. Mediated 214 -0.020 (-0.217, 0.096) 0.7 — — —
Bisphenol S, Trimester 3, Male, SEPAGES
Indirect effect 194 -0.000 (-0.030, 0.019) >0.9 — — —
Direct effect 194 0.130 (-0.094, 0.380) 0.3 — — —
Total Effect 194 0.130 (-0.094, 0.376) 0.3 — — —
Prop. Mediated 194 -0.004 (-0.516, 0.531) >0.9 — — —
Butylparaben, Trimester 2, Female, BiSC
Indirect effect 195 0.010 (-0.050, 0.068) 0.8 — — —
Direct effect 195 -0.234 (-0.621, 0.188) 0.3 — — —
Total Effect 195 -0.223 (-0.620, 0.196) 0.3 — — —
Prop. Mediated 195 -0.046 (-0.620, 0.752) 0.9 — — —
Butylparaben, Trimester 2, Female, SEPAGES
Indirect effect 154 -0.025 (-0.093, 0.026) 0.3 — — —
Direct effect 154 -0.263 (-0.579, 0.083) 0.12 — — —
Total Effect 154 -0.288 (-0.622, 0.075) 0.10 — — —
Prop. Mediated 154 0.087 (-0.301, 0.489) 0.4 — — —
Propylparaben, Trimester 2, Female, BiSC
Indirect effect — — — 195 0.003 (-0.003, 0.015) 0.4
Direct effect — — — 195 -0.012 (-0.071, 0.049) 0.7
Total Effect — — — 195 -0.009 (-0.067, 0.053) 0.8
Prop. Mediated — — — 195 -0.306 (-1.692, 2.369) 0.9
Propylparaben, Trimester 2, Female, SEPAGES
Indirect effect — — — 154 -0.007 (-0.019, 0.002) 0.2
Direct effect — — — 154 -0.051 (-0.099, 0.001) 0.058
Total Effect — — — 154 -0.058 (-0.107, -0.004) 0.032
Prop. Mediated — — — 154 0.113 (-0.088, 0.548) 0.2