Acetaminophen (Neuro-developmental outcomes) updated on 07-16-2024

ADHD (Attention deficit hyperactivity disorder): Diagnosis/Risk

R analysis
id Study   Lib. in paper Exposition period    Study type 
 Control type 
 
Tags OR 95%CI x1/n1 x0/n0 no cases no exposed ROB Ref.
S16219
R67824		 Ahlqvist (Population-Based), 2024 Attention-deficit/hyperactivity disorder (ADHD) - ICD-10 (F90) or ICD-9 (314) - Median (IQR) follow-up of 13.4 (7.6-19.8) years during pregnancy (anytime or not specified) population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Paracetamol use: maternal ITW/questionnaires during pregnancy 1.07 [1.05;1.10] 12,834/185,909   133,552/2,294,888 146,386 185,909
ref
S16218
R67825		 Ahlqvist (Sibling), 2024 Attention-deficit/hyperactivity disorder (ADHD) - ICD-10 (F90) or ICD-9 (314) - Median (IQR) follow-up of 13.4 (7.6-19.8) years during pregnancy (anytime or not specified) population based cohort retrospective sibling excluded Adjustment: Yes Control group: Sibling Paracetamol use: maternal ITW/questionnaires during pregnancy 0.98 [0.94;1.02]
excluded (control group) 		8,526/-   87,679/- 96,205 -
ref
S16320
R67831		 Sznajder, 2022 Attention problems (> 80th percentile score) - Subscale of CBCL - At 3 years old during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: Yes Paracetamol use: maternal ITW/questionnaires during pregnancy 1.21 [1.01;1.45] 330/1,002   391/1,398 721 1,002
ref
S16220
R67826		 Chen, 2019 Diagnoses of ADHD (ICD-9-CM code: 314) by board-certified psychiatrists on the basis of diagnostic interviews and clinical judgement - Age 0 - 15 years old (mean diagnosis 3.71) during pregnancy (anytime or not specified) nested case control unexposed (general population or NOS) Adjustment: Yes Paracetamol use: prescription or medical files 1.20 [1.01;1.42] 676/3,236   274/1,514 950 3,236
ref
S16276
R67832		 Tovo-Rodrigues, 2018 Hyperactivity/inattention - Strengths and Difficulties Questionnaire (SDQ score ≥ 7 pts), Psychologists administration to parents - At 11 years old during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: Yes Paracetamol use: maternal ITW/questionnaires after pregnancy 1.20 [0.96;1.49] 165/959   391/2,488 556 959
ref
S16253
R67828		 Ystrom or Gustavson (Gustavson 2021 - Sibling), 2017 Attention deficit hyperactivity disorder - ICD-10 code F90 - Between 0 and 18 years old (Exposed 1–7 days) during pregnancy (anytime or not specified) prospective cohort sibling excluded Adjustment: Yes Control group: Sibling Paracetamol use: maternal ITW/questionnaires during pregnancy 0.87 [0.70;1.08]
excluded (control group) 		-/6,490   -/12,080 - 6,490
ref
S16290
R67829		 Ystrom or Gustavson (Ystrom - Population-Based), 2017 Attention-deficit/hyperactivity (ADHD - diagnosis of hyperkinetic disorder (F90.0, F90.1, F90.8, or F90.9)) - At 3-15 years old. during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: Yes Paracetamol use: maternal ITW/questionnaires during pregnancy 1.12 [1.02;1.24] -/52,707   -/60,266 - 52,707
ref
S16275
R67827		 Liew, 2014 Hyperkinetic disorder diagnosis (ICD-10: F90.0-F90.9) - Mean age of children at the end of follow-up: 10.7 years (range, 8.2-13.4 years) during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: Yes Paracetamol use: maternal ITW/questionnaires during pregnancy 1.37 [1.19;1.59] 551/36,187   283/28,135 834 36,187
ref
Total 6 studies 1.17 [1.08;1.27] 149,447 280,000
x1: number of endpoints among exposed, n1: number of exposed; x0: number of endpoints among non exposed, n0: number of non exposed; C: calculated odds ratio from numbers of events and effectives

Forest plot

StudyTE95% CIn casesn exposedweightROBABCDEF Ahlqvist (Population-Based), 2024Ahlqvist, 2024 1 1.07[1.05; 1.10]146,386185,90929%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Sznajder, 2022Sznajder, 2022 1.21[1.01; 1.45]7211,00212%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: criticalROB mesure: criticalROB reporting: moderate Chen, 2019Chen, 2019 1.20[1.01; 1.42]9503,23613%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Tovo-Rodrigues, 2018Tovo-Rodrigues, 2018 1.20[0.96; 1.49]55695910%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: moderateROB mesure: criticalROB reporting: moderate Ystrom or Gustavson (Ystrom - Population-Based), 2017Ystrom or Gustavson, 2017 2 1.12[1.02; 1.24]-52,70721%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Liew, 2014Liew, 2014 1.37[1.19; 1.59]83436,18715%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Total (6 studies) I2 = 67% 1.17[1.08; 1.27]149,447280,0000.55.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Population-Based; 2: Ystrom - Population-Based;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.17[1.06; 1.28]148,497276,76471%NAAhlqvist (Population-Based), 2024 Sznajder, 2022 Tovo-Rodrigues, 2018 Ystrom or Gustavson (Ystrom - Population-Based), 2017 Liew, 2014 5 case control studiescase control studies 1.20[1.01; 1.42]9503,236 -NAChen, 2019 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.17[1.08; 1.27]149,447280,00067%NAAhlqvist (Population-Based), 2024 Sznajder, 2022 Chen, 2019 Tovo-Rodrigues, 2018 Ystrom or Gustavson (Ystrom - Population-Based), 2017 Liew, 2014 6 Tags Adjustment   - Yes  - Yes 1.17[1.08; 1.27]149,447280,00067%NAAhlqvist (Population-Based), 2024 Sznajder, 2022 Chen, 2019 Tovo-Rodrigues, 2018 Ystrom or Gustavson (Ystrom - Population-Based), 2017 Liew, 2014 6 Paracetamol use   - maternal ITW/questionnaires after p ...  - maternal ITW/questionnaires after pregnancy 1.20[0.96; 1.49]556959 -NATovo-Rodrigues, 2018 1   - maternal ITW/questionnaires during ...  - maternal ITW/questionnaires during pregnancy 1.16[1.05; 1.29]147,941275,80577%NAAhlqvist (Population-Based), 2024 Sznajder, 2022 Ystrom or Gustavson (Ystrom - Population-Based), 2017 Liew, 2014 4   - prescription or medical files  - prescription or medical files 1.20[1.01; 1.42]9503,236 -NAChen, 2019 1 All studiesAll studies 1.17[1.08; 1.27]149,447280,00067%NAAhlqvist (Population-Based), 2024 Sznajder, 2022 Chen, 2019 Tovo-Rodrigues, 2018 Ystrom or Gustavson (Ystrom - Population-Based), 2017 Liew, 2014 60.55.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-0.40.40.1350.000Ahlqvist (Population-Based), 2024Sznajder, 2022Chen, 2019Tovo-Rodrigues, 2018Ystrom or Gustavson (Ystrom - Population-Based), 2017Liew, 2014

Asymetry test p-value = 0.0284 (by Egger's regression)

slope=0.0457 (0.0152); intercept=1.8694 (0.5568); t=3.3573; p=0.0284

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 16253, 16218

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.17[1.08; 1.27]149,447280,00067%NAAhlqvist (Population-Based), 2024 Sznajder, 2022 Chen, 2019 Tovo-Rodrigues, 2018 Ystrom or Gustavson (Ystrom - Population-Based), 2017 Liew, 2014 6 siblingssiblings 0.97[0.91; 1.04]96,2056,49011%NAAhlqvist (Sibling), 2024 Ystrom or Gustavson (Gustavson 2021 - Sibling), 2017 20.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Masarwa (Attention deficit hyperactivity diso ...Masarwa (Attention deficit hyperactivity disorder (ADHD)) 1.31[1.23; 1.39]48%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT7 Masarwa (Attention deficit hyperactivity diso ...Masarwa (Attention deficit hyperactivity disorder (ADHD) _ Correcting for exposure misclassification) 1.91[0.04; 3.77]0%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT4 Masarwa (Attention deficit hyperactivity diso ...Masarwa (Attention deficit hyperactivity disorder (ADHD) _ Correcting for selection bias) 1.31[0.91; 1.71]0%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT4 Gou (Attention deficit/hyperactivity disorder)Gou (Attention deficit/hyperactivity disorder) 1.25[1.17; 1.34]26%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT8 Ricci (Attention deficit/hyperactivity disord ...Ricci (Attention deficit/hyperactivity disorder (ADHD) _ Adjusted for maternal and infant characteristics) 1.47[1.12; 1.92]80%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT4 Ricci (Attention deficit/hyperactivity disord ...Ricci (Attention deficit/hyperactivity disorder (ADHD) _ Adjusted for maternal, infant characteristics and indication) 1.34[1.15; 1.55]50%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT4 Ricci (Attention deficit/hyperactivity disord ...Ricci (Attention deficit/hyperactivity disorder (ADHD) _ Unadjusted) 1.32[1.20; 1.44]47%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT7 metaPregmetaPreg 1.17[1.08; 1.27]67%280,000----Ahlqvist (Population-Based), 2024 Sznajder, 2022 Chen, 2019 Tovo-Rodrigues, 2018 Ystrom or Gustavson (Ystrom - Population-Based), 2017 Liew, 2014 60.510.01.0