Table 3 Characteristics of studies on prenatal acetaminophen use and other neurodevelopmental disorders (NDDs)

Bertoldi, 2020

USA—Brazil

1999 and 2002, Project Viva; Pelotas 2015

Project Viva:

Exposure to acetaminophen in both 1st and 2nd trimester of pregnancy and early childhood cognitive outcomes:

Wide Range Achievement of Visual Motor Abilities (WRAVMA)—drawing: β = −1.53 (95% CI: −2.93, −0.13)

Exposure to acetaminophen during pregnancy:

WRAVMA—drawing:

β = −0.63 (95% CI: −1.20, −0.06)

Pelotas cohort:

Exposure to acetaminophen in both 1st and 2nd trimester of pregnancy and early childhood cognitive outcomes:

INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA): Total: β = 0.09 (95% CI: 0.02–0.16)

Cohorts

Project Viva: N = 1,217

Pelotas: N = 3,818

To address the issue of missing outcome data, they implemented inverse probability weighting; they did not use multiple imputation because most covariates had < 5% missing values

Project Viva: Single pregnancies, who had intention to remain in the geographical area, were fluent in English, and presented by the 22nd week of gestation

Pelotas: Gave birth in any of five maternity hospitals of the city in 1 January–31 December 2015 and lived in the urban area

Project Viva: Mothers were asked to categorize their acetaminophen use during this pregnancy for the early pregnancy interview and in the past 3 months for the mid-pregnancy interview

Pelotas: Women were asked about any medication use during pregnancy at prenatal and perinatal interviews

Project Viva: Children's cognition using the Peabody Picture Vocabulary Test (PPVT-III) and the Wide Range Achievement of Visual Motor Abilities (WRAVMA)

Pelotas: Children's cognitive development at a 24-month follow-up visit was evaluated using the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA)

Bornehag, 2018

Switzerland

2007–2010

Odds ratio (OR) for language delays among girls whose mothers reported > 6 vs. 0 acetaminophen tablets during pregnancy: OR = 5.92 (95% CI: 1.10–31.94)

OR for LD in girls whose mothers’ urinary APAP was in the highest compared to the lowest quartile: OR = 10.34 (95% CI: 1.37–77.86)

Cohort

N = 754

NA

Pregnant women who could read Swedish and were not planning to move out of the country

Two exposure measures were used: (1) maternally reported number of acetamoniphen tablets taken between conception and enrollment; (2) acetaminophen urinary concentration at enrollment

Nurse evaluation and parental questionnaire on language use at 30 months of age

Brandlistuen, 2013 (overall study)

Norway

1999–2008

Prenatal paracetamol for > 28 days:

Poorer gross motor development: β = 0.05 (95% CI: 0.002–0.11)

Poor communication: β = 0.08 (95% CI: 0.02–0.14)

Poor externalizing behaviour: β = 0.13 (95% CI: 0.07–0.18)

Poor internalizing behaviour: β = 0.03 (95% CI:−0.03– 0.08)

Higher activity levels: β = 0.001 (95% CI: −0.05–0.04)

Short- term use of paracetamol (1–27 days):

Poor gross motor outcomes: β = 0.03 (95% CI: 0.01– 0.05)

Prospective cohort

26,613

Multiple imputation

NA

Information on paracetamol use was obtained from two prenatal questionnaires; groups were divided in short-term (1–28 days of use) and long-term (≥ 28 days)

Psychomotor development: Norwegian version of the Ages and Stages Questionnaire (ASQ)

Externalizing and internalizing behaviours: Child Behaviour Checklist (CBCL/ 11/2–5/LDS) Temperament: Emotionality, Activity and Shyness Temperament Questionnaire (EAS)

Brandlistuen, 2013 (sibling control study)

Norway

1999–2008

Prenatal paracetamol for > 28 days:

Poorer gross motor development: β = 0.24 (95% CI: 0.12–0.51)

Poor communication: β = 0.20 (95% CI: 0.01–0.39)

Poor externalizing behaviour: β = 0.28 (95% CI: 0.15–0.42)

Poor internalizing behaviour: β = 0.14 (95% CI: 0.01– 0.28)

Higher activity levels: β = 0.24 (95% CI: 0.11–0.38)

Short- term use of paracetamol (1–27 days):

Poor gross motor outcomes: β = 0.10 (95% CI: 0.02– 0.19)

Prospective cohort

N = 2,919 same-sex sibling pairs

Multiple imputation

NA

Information on paracetamol use was obtained from two prenatal questionnaires; groups were divided in short-term (1–28 days of use) and long-term (≥ 28 days)

Psychomotor development: Norwegian version of the Ages and Stages Questionnaire (ASQ)

Externalizing and internalizing behaviours: Child Behaviour Checklist (CBCL/ 11/2–5/LDS) Temperament: Emotionality, Activity and Shyness Temperament Questionnaire (EAS)

Golding, 2019

UK

1991–1992

Mean differences in cognition and behaviour measures and paracetamol exposure at 18–32 weeks gestation: IQ—Freedom from distractibility at 8 years: Adjusted mean difference (AMD) = −0.35 (95% CI: −0.69, −0.00) M.SDQ Hyperactivity at 42 months: AMD = 0.16 (95% CI: 0.07–0.25) M.SDQ Hyperactivity at 47 months: AMD = 0.22 (95% CI: 0.10–0.33) Development and Well‐being Assessment (T.DAWBA) Attention at 7–8 years: AMD = 0.45 (95% CI: 0.11–0.79) T.DAWBA Attention/ Activity at 7–8 years: AMD = 0.53 (95% CI: 0.02–1.04)

Cohort

N = 12,418

NA

Pregnant women who were residents in Avon, UK, with at least one questionnaire returned and no misscarriage

Questionnaire at ~ 32 weeks gestation

Strengths and Difficulties Questionnaire (SDQ); 18 measures of cognitive function considered, 11 relating to IQ (not clear what test they used); 11 measures of the child's temperament (not clear)

Inoue, 2021

Denmark

23

Risk ratios (RR) for behavioral difficulties at age 11 years: Parent reported: Strengths and Difficulties Questionnaire (SDQ)—composite score: RR = 1.14 (95% CI: 1.01–1.29) Internalizing: RR = 1.09 (95% CI: 1.00–1.19) SDQ—Emotional symptoms: RR = 1.16 (95% CI: 1.09–1.24) Hyperactivity: RR = 1.12 (1.02–1.24) Child-reported: Strengths and Difficulties Questionnaire (SDQ)—composite score: RR = 1.40 (95% CI: 1.20–1.63) Internalizing: RR = 1.13 (95% CI: 1.04–1.23) Externalizing: RR = 1.13 (95% CI: 1.05–1.22) SDQ—Emotional symptoms: RR = 1.17 (95% CI: 1.02–1.34) Hyperactivity: RR = 1.18 (1.08–1.29)

Cohort

N = 40,934

Multiple imputation (10 simulated complete datasets were generated assuming multivariate normal distribution for about 8% of participants who had at least 1 missing covariate value)

Mothers, with live-born children, who answered the study enrollment form and three subsequent telephone interviews (12th and 30th gestational weeks and at 6 months after birth)

Information about acetaminophen exposure was obtained from the study enrollment form and three computer-assisted telephone interviews

Children’s behaviors were assessed based on the standardized Strengths and Difficulties Questionnaire (SDQ)

Laue, 2019

Canada

2007–2009

Estimates for the association between prepregnancy acetaminophen exposure and neurocognitive development: Coding: Low exposure: 1.03 (95% CI: −0.22–2.29) High exposure: 0.74 (95% CI: −0.54–2.01) Block Design subtest: Low exposure: 1.03 (95% CI: −0.22–2.29) High exposure: −0.92 (95% CI: −2.20–0.37)

Cohort

N = 118

Excluded

Pregnant women living in Sherbrooke, Quebec, Canada recruited in 2007–2009 during the first trimester of pregnancy and at delivery

Acetaminophen was extracted from < 120 mg meconium by solid–liquid extraction in ethyl acetate followed by purification

with a dispersive solid phase extraction in acetonitrile

Neurocognitive development was evaluated using the Wechsler Intelligence Scale for Children, 4th edition (WISC-IV)

Liew, 2016

Denmark

1996–2002

Prenatal acetaminophen and IQ: Mean difference in full-scale IQ in 1–5 weeks of use: −3.1 (95% CI: −5.6,−0.68) Mean difference in performance IQ in 1–5 weeks of use: −4.1 (95% CI: −7.3, −0.88)

Cohort

N = 1,491

Multiple imputation

Sampling was based on maternal alcohol and binge drinking reported during pregnancy with an oversampling strategy; women who spoke insufficient Danish or did not intend to complete their pregnancy were excluded

Information about acetaminophen use was collected in three telephone interviews conducted at gestational weeks 12 and 30

Child IQ was assessed using the Wechsler Primary and Preschool Scales of intelligence-revised (WPPSi-r); the cohort used a shorter version that includes three verbal and three performance sub-tests designed to shorten test duration

Parker, 2020

USA and Canada

1996–2002

Any use of acetaminophen was associated with mother-reported behavioral problems (mean differences [MD] = 2.2 [95% CI: 0.3–4.1]) MD was similar for both internalizing (MD = 2.5 [95% CI: 0.8–4.3]) and externalizing (MD = 1.9 [95% CI: 0.1–3.7]) broadband scales

Cohort

N = 560

NA

Data on maternal exposures during pregnancy and at least one neurodevelopmental assessment in childhood

Standardized interview administered after delivery and prior to childhood neurodevelopmental assessments

The Child Behavior Checklist (CBCL) and Teacher-Report Form (TRF), tests that are part of the Achenbach System of Empirically Based Assessment (ASEBA), were used to assess common child behavior problems

Rifas-Shiman, 2020

USA

1999–2002

Behaviour Rating Inventory of Executive Function (BRIEF) Global Executive Composite: β = 1.64 (95% CI: 0.59–2.68) Behaviour Regulation Index: β = 1.45 (95% CI: 0.44–2.47) BRIEF Metacognition Index: β = 1.29 (95% CI: 0.29–2.30) Infancy exposure (≥ 6 versus < 6 times) to acetaminophen and higher parent-rated BRIEF—Global Executive Composite score (GEC) scores: BRIEF—Global Executive Composite: β = 1.69 (95% CI: 0.51–2.87) Behaviour Regulation Index: β = 1.26 (95% CI: 0.08–2.45) BRIEF Metacognition Index: β = 1.67 (95% CI: 0.54–2.81) Strengths and Difficulties Questionnaire (SDQ) Total Difficulties: β = 1.19 (95% CI: 0.58–1.80)

Cohort

N = 1,225

Multiple imputation

Women with single pregnancies, who had intention to remain in the geographical area, were fluent in English, and presented by the 22nd week of gestation

Mothers were asked to categorize their acetaminophen use during this pregnancy for the early pregnancy interview (1st trimester) and in the past 3 months for the mid-pregnancy interview (2nd trimester)

Behavoiur Rating Inventory of Executive Function (BRIEF) and the Strengths and Difficulties Questionnaire (SDQ)

Ruisch, 2018

UK

1991–1992

Paracetamol exposure during pregnancy and oppositional-defiant disorder (ODD) and conduct disorder (CD) symptoms: ODD scores—Teacher rated: Incidence rate ratio (IRR) = 1.21 (95% CI: 1.06–1.38) CD symptom scores—Maternal rated: IRR = 1.14 (95% CI: 1.05–1.24) CD symtom scores—Teacher rated: IRR = 1.25 (95% CI: 1.01–1.53)

Cohort

N≈6,300 for maternal and N≈4,400 for teacher ratings

NA

Pregnant women who were residents in Avon, UK, with at least one questionnaire returned and no misscarriage

Questionnaires at 18 weeks gestation

Development and Well-Being Assessment (DAWBA)

Skovlund, 2017

Norway

1999–2008

Odds ratios of having a child with lower communication skills according to use of paracetamol: Two periods (trimesters): adjusted OR = 1.09 (95% CI: 1.04–1.15) Three periods (trimesters): Adjusted OR = 1.17 (95% CI: 1.06–1.30)

Cohort

N = 58,410

Excluded

Pregnant women in Norway who agreed to participate prior to first ultrasound scan at weeks 17–18

Mothers were asked to report on medication use at pregnancy weeks 17–18 and 30

Language competence at 3 years of age was evaluated by a validated language grammar rating scale (Dale, 2003; PMID: 14,696,985)

Streissguth, 1987

Seattle, USA

1974–1975

IQ scores on aspirin and acetaminophen: Linear model: β(SE) = 0.28 (0.54); p = 0.61 Binary model: β(SE) = 0.37 (0.54); p = 0.49

Cohort

N = 421

NA

A consecutive group of pregnant women receiving prenatal care in 1974–1975, interviewed during the 5th month of pregnancy in their own homes

Self-report at 5 months gestation

Child IQ assessed with the Weschler Preschool and Primary Scale of Intelligence (WPPSD)

Tovo-Rodrigues, 2020

Brazil

2004

Acetaminophen during pregnancy and neurodevelopmental performance: Low performance in BDI: RR = 1.00 (95% CI: 0.78–1.28) Social-personal area: RR = 1.00 (95% CI: 0.80–1.25) Adaptative area: RR = 0.91 (95% CI: 0.76–1.08) Motor area: RR = 0.91 (95% CI: 0.71–1.16) Communication area: RR = 1.04 (95% CI: 0.84–1.30) Cognitive area: RR = 0.92 (95% CI: 0.83–1.02)

Cohort

N = 3,737

Missing data were handled using inverse probability weighting

Mothers were those living in the urban area of Pelotas or in Jardim América

Standardised questionnaire applied at the perinatal evaluation; use of acetaminophen was defined as at least once during pregnancy, regardless of the dose used

The screening version of Battelle's Developmental Inventory (BDI) was used to assess children development at 24 months of age Child behavioral/emotional problems were assessed at 48 months using the Child Behaviour Checklist (CBCL)

Tronnes, 2020

Norway

1999–2008

Paracetamol exposure during pregnancy and behavioral problems in preschool-age: Paracetamol use in three trimesters: adjusted RR = 1.36 (95% CI: 1.02–1.80) Paracetamol exposure during pregnancy and temperamental traits: Paracetamol use in two trimesters—Shyness: adjusted RR = −0.62 (95% CI: − 1.05, − 0.19)

Cohort

N = 32,934

NA (not even in supplementary material)

Pregnant women at their routine ultrasound examination at gestational week 17–18

Information about medication use was obtained from two prenatal questionnaires

Communication skills were assessed by the Ages and Stages Questionnaire (ASQ) Selected items from the Child Behaviour Checklist (CBCL) for preschool children (CBCL/ 1.5–5) were used to assess children’s behavior Temperament was assessed by the short version of the Emotionality, Activity and Shyness Temperament Questionnaire (EAS)

Vlenterie, 2016

Norway

1999–2008

Paracetamol exposure and psychomotor and behavioural outcomes in 18-month-old infants: Psychomotor problems: Fine motor: OR = 1.17 (95% CI: 1.01–1.36) Delayed motor milestone attainment: OR = 1.35 (95% CI: 1.07–1.70) Communication: OR = 1.32 (95% CI: 1.05–1.66) Behavioural problems: Externalizing: OR = 1.50 (95% CI: 1.26–1.76)

Cohort

N = 51,200

NA

Pregnant women at their routine ultrasound examination at gestational week 17–18

Information about medication use was obtained from two prenatal questionnaires

Woodbury, 2024

Illinois, USA

Pregnancies:2013–2020

Vocabulary (CDI) β = −0.58 (95% CI −1.13, −0.04) 2nd Trimester, β = −1.83 (−3.13, −0.54) 3rd trimester. Mean length of utterance(CDI) β = −0.01 (−0.01, 0.001) 2nd trimester, B = −0.02 (−0.04,−0.003) 3rd trimester

Prospective cohort

N = 532

Exclusion

18–40 year old English speaking pregnant women invited at 1st prenatal visit, not yet 15 weeks gestation, no other children in cohort, resided nearby, carrying singleton, considered low risk, plan to remain in area until child's 1st birthday

Maternal interview at 6 time points. 5 during pregnancy and 1 at birth

Early language development evaluated using the MacArthur-Bates Communicative Development Inventories: Words and Sentences (CDI) and the Speech and Language Assessment Scale (SLAS)

Zhou, 2024

Beijing, China

2018–2024

No risk estimate provided but stated APAP was associated with gross motor. Mean SHAP value for Gross Motor 0.073 (interpretable machine language method calculate SHapley Additive exPlanations (SHAP) to explain variable contribution in the predictive model)

Prospective cohort

N = 1125

Exclusion also interpolated maternal missing data using either the multitude or median and for offspring interpolated using the mean of the other area scores for that individual

Singleton, live births with data regarding maternal medication usage and completion of ASQ-3 questionnaire in 1st year

In-patient and out-patient prescription data prescribed from the start of last menstrual period until delivery

Parent administered, Chinese Ages and Stages Questionnaire-3 (ASQ-3) assessing communication, gross motor, fine motor, problem solving & person-social in first year