Supplementary Online Content

Liew Z, Ritz B, Rebordosa C, Lee P-C, Olsen J. Acetaminophen use during

pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr.
Published online February 24, 2014. doi:10.1001/jamapediatrics.2013.4914.

eTable 1. Crude and Adjusted Regression Coefficients (β) for Parents’ Rated
SDQ Total Difficulties Scores (Continuous) in Children at the Age of 7 Years and
Maternal Acetaminophen Use During Pregnancy

eTable 2. Hazard Ratios (HRs) for Hyperkinetic Disorders Hospital Diagnosis or

ADHD Medication Redemption According to Maternal Acetaminophen Use
During Pregnancy, Stratified by Potential Indications of Acetaminophen Use

eTable 3. Hazard Ratios (HRs) for Hyperkinetic Disorders Diagnosis and

Medication Redemption According to Maternal Acetaminophen Use During
Pregnancy

eTable 4. Associations of ADHD-Like Behavioral Problem, Hyperkinetic

Disorders Hospital Diagnosis or ADHD Medication Use in Children According to
Number of Weeks of Acetaminophen Use Stratified by Pregnancy Trimesters

eTable 5. Hazard Ratios (HRs) for Hyperkinetic Disorders Hospital Diagnosis or

Medication Redemption and Maternal Acetaminophen Use During Pregnancy, by
Sex of the Child

eTable 6. Hazard Ratios (HRs) for Hyperkenetic Disorders According to

Maternal Use of Acetaminophen, With Further Adjustment for Maternal Use of
Common NSAIDs and Type of Maternal Mental Health Illnesses

This supplementary material has been provided by the authors to give readers
additional information about their work.

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 eTable 1. Crude and Adjusted Regression Coefficients (β) for Parents’ Rated SDQ Total Difficulties
Scores (Continuous) in Children at the Age of 7 Years and Maternal Acetaminophen Use During
Pregnancy
Use of acetaminophen during pregnancy Crude β Adjusted βa 95% CI p-value
outcome of SDQ total difficulties scores as its original scale range 0-40b
Ever versus never use 0.497 0.243 0.162-0.325 <0.0001
One week increase of usage 0.031 0.018 0.012-0.024 <0.0001
outcome of natural log-transform original SDQ total difficulties scores + 1
Ever versus never use 0.083 0.048 0.035-0.061 <0.0001
One week increase of usage 0.005 0.003 0.002-0.004 <0.0001
a
Adjusted maternal age at birth, gender of child, child’s birth year, gestational age, birth weight, parity, socio-economic status of mother, maternal
smoking and alcohol drinking during pregnancy, maternal pre-pregnancy body mass index, parent’s behavioral scores in childhood, mother's ever had
mental health problems, and maternal diseases in muscles/joints, fever, or infection/inflammation during pregnancy.
b
A high SDQ total difficulties scores indicate behavioral problems in children

   

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eTable 2. Hazard Ratios (HRs) for Hyperkinetic Disorders Hospital Diagnosis or ADHD Medication Redemption  
According to Maternal Acetaminophen Use During Pregnancy, Stratified by Potential Indications of Acetaminophen
Use  

Hospital diagnosed HKD ADHD Medication  

Use of acetaminophen during No. Cases Crude Adjusted HRa No. Cases Crude Adjusted HRa
pregnancy (Person-years) HR (95% CI) (Person-years) HR (95% CI)
 

Among mothers that never had psychiatric illnesses  

Never used 229 (139,418) 1.00 1.00 (ref) 384 (149,108) 1.00 1.00 (ref)
Ever used 386 (170,403) 1.38 1.28 (1.08-1.51) 613 (182,123) 1.31 1.21 (1.07-1.38)  
In all three trimesters 80 (29,765) 1.63 1.48 (1.14-1.92) 133 (31,806) 1.62 1.47 (1.21-1.80)
 
Among mothers that did not have fever, inflammation
and infections during pregnancy  
Never used 205 (112,679) 1.00 1.00 (ref) 341 (120,562) 1.00 1.00 (ref)
 
Ever used 334 (120,478) 1.52 1.37 (1.15-1.63) 522 (128,767) 1.43 1.30 (1.13-1.49)
In all three trimesters 68 (21,022) 1.77 1.56 (1.18-2.06) 100 (22,491) 1.57 1.41 (1.12-1.77)  

Among mothers that did not have disease in muscles  

and joints during pregnancy
Never used 258 (145,024) 1.00 1.00 (ref) 434 (155,144) 1.00 1.00 (ref)  
Ever used 430 (175,467) 1.38 1.25 (1.07-1.46) 706 (187,536) 1.35 1.23 (1.09-1.39)
In all three trimesters 84 (29,778) 1.58 1.40 (1.09-1.80) 135 (31,842) 1.51 1.35 (1.11-1.64)  
a
Adjusted maternal age at birth, gender of child, child’s birth year, gestational age, birth weight, parity, socio-economic status of mother, maternal smoking and alcohol  
drinking during pregnancy, maternal pre-pregnancy body mass index, mother's ever had mental health problems, and maternal diseases in muscles/joints, fever, or
infection/inflammation during pregnancy.
 

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 eTable 3. Hazard Ratios (HRs) for Hyperkinetic Disorders Diagnosis and
Medication Redemption According to Maternal Acetaminophen Use
During Pregnancy
Hyperkinetic Disorders and redeemed
medications at least twice

No. Cases Crude Adjusted HRa

Prenatal exposure and timing (Person-years) HR (95% CI)

Acetaminophen use during pregnancy

Never used 217 (159,308) 1.00 1.00 (ref)
Ever used 444 (204,192) 1.59 1.44 (1.22-1.69)
All three trimester 100 (16,363) 2.00 1.78 (1.40-2.26)
Weeks of acetaminophen use
throughout pregnancy
0 weeks 217 (159,308) 1.00 1.00 (ref)
1 week 102 (51,551) 1.45 1.35 (1.07-1.72)
2-5 weeks 94 (49,340) 1.38 1.28 (1.00-1.64)
6-10 weeks 35 (13,039) 1.94 1.72 (1.19-2.48)
11-20 weeks 35 (12,361) 2.06 1.77 (1.23-2.54)
>20 weeks 51 (16,363) 2.27 2.06 (1.51-2.82)
p-trend < 0.0001
a
Adjusted maternal age at birth, gender of child, child’s birth year, gestational age, birth weight, parity, socio-
economic status of mother, maternal smoking and alcohol drinking during pregnancy, maternal pre-pregnancy
body mass index, mother's ever had mental health problems, and maternal diseases in muscles/joints, fever,
or infection/inflammation during pregnancy.
† Week of acetaminophen use is modeled as a continuous variable in trend test.

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 eTable 4. Associations of ADHD-Like Behavioral Problem, Hyperkinetic Disorders Hospital Diagnosis or ADHD Medication
Use in Children According to Number of Weeks of Acetaminophen Use Stratified by Pregnancy Trimesters
SDQ total difficulties
(scores≥17) Hospital diagnosed HKD HKD Medication

No. Cases / Adjusted RRa No. Cases Adjusted HRa No. Cases Adjusted HRa
Prenatal exposure and timing non-cases (95% CI) (Person-years) (95% CI) (Person-years) (95% CI)
Weeks of acetaminophen use
throughout pregnancy, by trimesters
281 477
Never used 457 / 17723 1.00 (ref) (159,149) 1.00 (ref) (170,196) 1.00 (ref)
First Trimesters
1.04 (0.87- 1.21 (1.02-
Used acetaminophen 1-6 weeks 179 / 5686 1.24) 127 (47,840) 1.37 (1.10-1.70) 194 (51,452) 1.44)
Used acetaminophen 7-12 1.37 (1.11- 1.37 (1.11-
weeks 110 / 2481 1.70) 83 (23,227) 1.73 (1.35-2.23) 111 (24,823) 1.69)
Second Trimesters
1.10 (0.93- 1.27 (1.08-
Used acetaminophen 1-6 weeks 209 / 6344 1.30) 144 (57,076) 1.30 (1.06-1.59) 240 (61,105) 1.48)
Used acetaminophen 7-12 1.44 (1.16- 1.44 (1.16-
weeks 105 / 2168 1.80) 74 (20,597) 1.79 (1.37-2.33) 104 (21,996) 1.80)
Third Trimesters
1.17 (1.00- 1.41 (1.22-
Used acetaminophen 1-6 weeks 276 / 7206 1.36) 183 (65,905) 1.40 (1.15-1.70) 317 (71,036) 1.63)
Used acetaminophen 7-18 1.30 (1.00- 1.64 (1.31-
weeksb 70 / 1424 1.69) 50 (13,363) 1.87 (1.37-2.54) 94 (17,436) 2.05)

Additional week of acetaminophen

use, by trimesters
1.03 (1.00- 1.03 (1.01-
First trimesters - 1.05) - 1.05 (1.03-1.07) - 1.05)
1.03 (1.01- 1.03 (1.01-
Second trimesters - 1.05) - 1.05 (1.03-1.08) - 1.05)
1.04 (1.02- 1.05 (1.03-
Third trimesters - 1.06) - 1.06 (1.03-1.08) - 1.07)

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 a
Adjusted maternal age at birth, gender of child, socio-economic status of mother, gestational age, birth weight, maternal smoking during pregnancy, maternal alcohol drinking during
pregnancy, parity, child’s birth year, mother's ever had mental health problems, and maternal diseases in muscles/joints, fever, or infection/inflammation during pregnancy.
b
Used acetaminophen for 7 or more weeks until delivery

eTable 5. Hazard Ratios (HRs) for Hyperkinetic Disorders Hospital Diagnosis or Medication Redemption and
Maternal Acetaminophen Use During Pregnancy, by Sex of the Child
Hospital diagnosed HKD ADHD Medication

No. Cases Crude Adjusted HRa No. Cases Crude Adjusted HRa
Prenatal exposure and timing (Person-years) HR (95% CI) (Person-years) HR (95% CI)
Boys
Acetaminophen use during pregnancy
Never used 237 (81,694) 1.00 1.00 (ref) 387 (87,235) 1.00 1.00 (ref)
Ever used 433 (103,221) 1.45 1.29 (1.09-1.51) 693 (109,973) 1.42 1.26 (1.11-1.43)
1st trimester only 74 (17,956) 1.42 1.35 (1.04-1.75) 101 (19,162) 1.19 1.12 (0.90-1.40)
2nd trimester only 35 (9,158) 1.32 1.25 (0.88-1.78) 55 (9,773) 1.27 1.19 (0.90-1.58)
3rd trimester only 81 (21,207) 1.32 1.13 (0.88-1.46) 141 (22,607) 1.41 1.22 (1.00-1.48)
All three trimesters 96 (18,103) 1.82 1.55 (1.22-1.98) 149 (19,308) 1.74 1.49 (1.23-1.80)

Girls
Acetaminophen use during pregnancy
Never used 46 (77,515) 1.00 1.00 (ref) 91 (83,029) 1.00 1.00 (ref)
Ever used 118 (100,821) 1.97 1.79 (1.26-2.54) 184 (107,972) 1.55 1.40 (1.08-1.81)
1st trimester only 14 (16,931) 1.39 1.33 (0.73-2.42) 19 (18,127) 0.96 0.93 (0.57-1.52)
2nd trimester only 8 (9,557) 1.41 1.29 (0.60-2.75) 15 (10,238) 1.34 1.25 (0.72-2.16)
3rd trimester only 22 (20,211) 1.83 1.61 (0.95-2.72) 41 (21,655) 1.73 1.54 (1.05-2.24)
All three trimesters 24 (18,359) 2.20 1.96 (1.17-3.26) 32 (19,672) 1.48 1.27 (0.84-1.92)

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 a
Adjusted maternal age at birth, child’s birth year, gestational age, birth weight, parity, socio-economic status of mother, maternal smoking and alcohol drinking during
pregnancy, maternal pre-pregnancy body mass index, mother's ever had mental health problems, and maternal diseases in muscles/joints, fever, or infection/inflammation
during pregnancy.

eTable 6. Hazard Ratios (HRs) for Hyperkenetic Disorders According to Maternal Use of Acetaminophen, With
Further Adjustment for Maternal Use of Common NSAIDs and Type of Maternal Mental Health Illnesses
Model A Model B Model C
Use of acetaminophen
during pregnancy Crude HR Adjusted HRa (95% CI) Adjusted HRb (95% CI) Adjusted HRc (95% CI)
Never used 1.00 1.00 (ref) 1.00 (ref) 1.00 (ref)
Ever used 1.52 1.40 (1.21-1.62) 1.39 (1.21-1.61) 1.37 (1.18-1.58)
All three trimesters 1.84 1.66 (1.33-2.06) 1.65 (1.33-2.05) 1.61 (1.30-2.01)
a
Model A: adjusted maternal age at birth, gender of child, child’s birth year, gestational age, birth weight, parity, socio-economic status of mother, maternal smoking
and alcohol drinking during pregnancy, maternal pre-pregnancy body mass index, and maternal diseases in muscles/joints, fever, or infection/inflammation during
pregnancy.
b
Model B: adjusted all in a plus maternal use of ibuprofen and aspirin during pregnancy.
c
Model C: adjusted all in a plus mother's ever had depression, anxiety, childhood psychiatric disorder, family problems/life crisis, or other mental health problems.
d
In DNBC study cohort 1 (n=64,322), about 56.3% mothers ever used acetaminophen, 4.5% ever used aspirin, and 5.1% ever used ibuprophen during pregnancy.
Among acetaminophen users (n=36,187), about 4.9% also used aspirin and 5.9% used ibuprophen.
e
In DNBC study cohort 1 (n=64,322), percentages of maternal mental health illnesses as following: depression (6.6%), anxiety (2.6%), childhood psychiatric disorder
(0.3%), family problems/life crisis (2.8%), or other mental health problems (5.6%).

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