Acetaminophen (Neuro-developmental outcomes)

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Ahlqvist (Population-Based), 2024	population based cohort retrospective	1995-2019: Prospective collection during the first antenatal visit (typically at 8-10 weeks’ gestation), during which midwives conducted structured interviews (including OTC), and later in pregnancy by the midwife and physician. From 2005: supplemented with Prescribed Drug Register.	Autism, ADHD, and intellectual disability diagnoses were identified using International Classification of Diseases (ICD) codes from the National Patient Register. ADHD diagnoses were also identified based on the dispensation of the ADHD medications (methylphenidate or atomoxetine).	Singleton. Adjusted for child sex; all other analgesics; parent’s diagnoses of migraine, chronic pain, infections, fever, rheumatoid arthritis, and headaches; parity; age; cohabitation at delivery; BMI; smoking; use of psycholeptics, antidepressants, and antiseizure medication; ...; household education and disposable income.
Ahlqvist (Sibling), 2024	population based cohort retrospective	1995-2019: Prospective collection during the first antenatal visit (typically at 8-10 weeks’ gestation), during which midwives conducted structured interviews (including OTC), and later in pregnancy by the midwife and physician. From 2005: supplemented with Prescribed Drug Register.	Autism, ADHD, and intellectual disability diagnoses were identified using International Classification of Diseases (ICD) codes from the National Patient Register. ADHD diagnoses were also identified based on the dispensation of the ADHD medications (methylphenidate or atomoxetine).	Singleton. Sibling (genetic, environment, history of neurodev disorders). Adjusted for child sex; all other analgesics; parent’s diagnoses of migraine, chronic pain, infections, fever, rheumatoid arthritis, and headaches; parity; age; cohabitation at delivery; BMI; smoking; use of psycholeptics, antidepressants, and antiseizure medication; ...; household education and disposable income.
Alemany_DNBC, 2021	prospective cohort	Paracetamol use was collected in three computer-assisted telephone interviews conducted at gestational weeks 12 and 30 and 6 months postpartum. At each interview, mothers were asked if they had taken acetaminophen as a singular or combination drug available over the counter or via prescription.	The autistic traits were assessed using the Strengths and Difficulties Questionnaire (SDQ - 25 items), completed by mothers. Abnormal scores in emotional problems and in peer problems or prosocial behaviour SDQ subscales were recommended to capture ASC symptoms.	Adjusted for maternal age, education, pre-pregnancy Body Mass Index, alcohol, prenatal smoking, mental health problems during pregnancy, parity, maternal fever and infections during pregnancy, parity, child sex and age at assessment.
Bertoldi_Pelotas, 2020	prospective cohort	Women were asked about any medications use during pregnancy at prenatal (before 16 weeks of gestation and at 16-24 weeks of gestation) and perinatal interviews (hours after delivery). Then, all drugs used were classified by trimester of use and number of days of use in each trimester.	Children cognitive development was evaluated using the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) administered mainly at the research clinic and sometimes in the child's home by interviewers trained by neurodevelopment professionals. INTER-NDA: good agreement with the Bayley Scale.	Only raw data can be extracted (adjusted β (95% CI) of linear regression cannot be reported here)).
Chen, 2019	nested case control	The Taiwan Longitudinal Health Insurance Database that contains comprehensive data on insured individuals, including prescriptions.	The Taiwan Longitudinal Health Insurance Database that contains comprehensive data on insured individuals, including clinical visit dates and disease diagnoses (ICD-9-CM are used for disease diagnosis).	Adjusted/matched for demographic data (age, sex, income, level of urbanization), gestational infections, comorbid perinatal conditions (including preterm or low birth weight, birth trauma, and intrauterine hypoxia/birth asphyxia) and for maternal mental health disorders. Sensitivity analysis excluding Gestational Infections and Maternal Mental Health Disorders => same significant associations.
Inoue, 2021	prospective cohort	Maternal acetaminophen use during pregnancy was ascertained from the study enrollment form and 3 computer-assisted telephone interviews (scheduled at approximately the 12th and 30th gestational weeks and at 6 months after birth), including acetaminophen as a single or combination drug.	Children’s behaviors were assessed based on the standardized Strengths and Difficulties Questionnaire (SDQ), completed by both parents and children.	Adjusted for maternal age, child’s birth year, parity, socio-occupational status, prepregnancy BMI, maternal smoking, alcohol drinking during pregnancy, mental health problems, maternal NSAIDs intake and diseases in muscles/joints, fever or infection/inflammation during pregnancy. Sensitivity for additional control for parental childhood behavioral problem scores (familial and genetic risks).
Liew, 2014	prospective cohort	Paracetamol use was collected in three computer-assisted telephone interviews conducted at gestational weeks 12 and 30 and 6 months postpartum. At each interview, mothers were asked if they had taken acetaminophen as a singular or combination drug available over the counter or via prescription.	Hyperkinetic disorders diagnosis identified from the National Hospital Registry, the Psychiatric Central Registry or 2 or more ADHD medication prescriptions (methylphenidate, atomoxetine or modafinil). ADHD-like behaviors based on the Strengths and Difficulties Questionnaire (parental report).	Adjusted for maternal age at birth, sex of child, child’s birth year, gestational age, birth weight, parity, socioeconomic status of mother, maternal smoking and alcohol drinking during pregnancy, maternal prepregnancy BMI, mother’s ever having had mental health problems, and maternal diseases in muscles/joints, fever, or infection/inflammation during pregnancy. Additional sensitivity analyses.
Liew a, 2016	prospective cohort	Paracetamol use was collected in three computer-assisted telephone interviews conducted at gestational weeks 12 and 30 and 6 months postpartum. At each interview, mothers were asked if they had taken acetaminophen as a singular or combination drug available over the counter or via prescription.	Child IQ was assessed with the Wechsler Primary and Preschool Scales of intelligence-revised (WPPSi-r) administered by trained psychologists.	Singleton only. Adjusted for parental education, maternal IQ, maternal smoking and drinking during pregnancy, parity, maternal age at child birth, child’s sex, maternal diseases in muscles/joints, fever, or infection/inflammation during pregnancy, and prenatal use of ibuprofen or aspirin. Sensitivity analysis excluding high alcohol drinkers or extreme child IQ values.
Liew b, 2016	prospective cohort	Paracetamol use was collected in three computer-assisted telephone interviews conducted at gestational weeks 12 and 30 and 6 months postpartum. At each interview, mothers were asked if they had taken acetaminophen as a singular or combination drug available over the counter or via prescription.	Autism Spectrum Disorder diagnosis (ICD-10) was ascertained by linking Danish National Birth Cohort to the Danish National Hospital Registry, which contains nationwide records for all somatic admissions, and the Danish Psychiatric Central Registry for admissions to psychiatric hospitals.	Singleton only. Adjusted for child’s sex, birth year, maternal age, parity, socio-economic status, maternal smoking and alcohol drinking during pregnancy, maternal prepregnancy body mass index, folic acid during pregnancy, mother’s psychiatric illnesses, maternal diseases in muscles/joints, fever, or infection/inflammation during pregnancy, maternal use of ibuprofen and aspirin during pregnancy.
Sznajder, 2022	prospective cohort	Data on medication use during pregnancy was collected during the first interview of participants, conducted by telephone during their third trimester of pregnancy (mean gestational age of 35.2 weeks). They were asked if it was prescription or non-prescription, the dose, frequency taken, and reason.	Child behavioral problems were measured using the 7 syndrome scale scores from the 99-item Child Behavior Checklist (CBCL) for ages 1 1⁄2 to 5, completed by parents. Pregnancy and neonatal complications were based on the ICD-9 codes in the hospital discharge data and from the birth certificates.	Exclusion of pregnancies delivered before 34 weeks gestation. Neurodevelopmental outcomes: adjusted for infection during pregnancy and/or maternal age and/or maternal race and/or alcohol consumption and/or diagnosis of anxiety or depression and/or stress and/or insurance coverage and/or cold/allergies and/or trouble sleeping and/or thyroid conditions and/or muscle pain and/or mode of delivery.
Tovo-Rodrigues, 2018	prospective cohort	A standardized questionnaire was used during the perinatal evaluation conducted after the birth of the children. The mothers were asked to report all medicines used during pregnancy, and the beginning and end of use.	Standardized scores from the Strengths and Difficulties Questionnaire (SDQ) adapted and previously validated for the Brazilian population 4-16 years. Trained psychologists administered the SDQ in a standardized manner to the parents or caregivers during each follow-up.	Exclusion of children who presented severe mental deficit due to problems such as cerebral palsy and Down syndrome. Adjusted for sex, maternal age, parity, national economic index, maternal educational level, maternal skin color, smoking, alcohol consumption during pregnancy, infection during pregnancy, pre-gestational BMI, maternal mood issue and use of other analgesics during pregnancy.
Tovo-Rodrigues, 2020	prospective cohort	Maternal use of medication during pregnancy was retrospectively assessed using a standardised questionnaire applied at the perinatal evaluation (within 24 hours after delivery).	At birth, the newborn was measured and had its gestational age assessed. At 24 and 48 months, the assessments were performed at the child's home (screening BDI and CBCL), in the presence of the mother or caregiver, by interviewers trained by a paediatrician or psychologist, respectively.	Adjusted for family wealth index; mother's skin colour; mother's age; mother's schooling; single mothers; parity; pre-pregnancy BMI; tobacco and alcohol use; and prenatal care (number of antenatal care appointments) during pregnancy, mood symptoms; infectious diseases; high blood pressure, gestational diabetes; use of other analgesics during pregnancy; and child sex.
Tronnes, 2020	prospective cohort	Information about medication use was obtained from two prenatal and one postnatal questionnaire completed by mothers (at gestational ages 17 and 30 weeks and at 6 months postpartum). Duration of paracetamol use was defined according to the number of trimesters it was used.	All outcomes were parent‐reported with: the Ages and Stages Questionnaire (ASQ) for communication skills; selected items from The Child Behaviour Checklist (CBCL) for children's behaviour and the Emotionality, Activity and Shyness Temperament Questionnaire (EAS) for temperament.	Exclusion of multiple pregnancies. Adjusted estimates are weighted with combined weights (IPTW × IPCW), including maternal age, martial status, education level, parity, pre‐pregnancy body mass index (BMI), folic acid supplement, smoking habits, alcohol use, symptoms of anxiety and depression, maternal health conditions during pregnancy, concomitant medication use, and child sex.
Vlenterie, 2016	prospective cohort	Women reported information about illnesses they experienced throughout pregnancy and the medication used for these illnesses, in the two prenatal and first post-partum questionnaire (at gestational week (GW) 17, GW30, and 6 months post-partum).	Outcomes were assessed by maternal assessment: psychomotor development by the Ages and Stages Questionnaire (ASQ); behaviour by the Child Behaviour Checklist (CBCL/11/2-5/LDS) and temperament with the short-form Emotionality, Activity and Shyness Temperament Questionnaire (EAS).	Singletons only. Exclusion of infants with major congenital malformations. Propensity score (PS) including maternal age, pre-pregnancy body mass index, parity, married/cohabiting, education, smoking, alcohol use, folate use, specific health conditions (pain, fever, infections, headache), psychotropic co-medication (opioids, antiepileptics, NSAIDs, ...) and depressive symptoms.
Woodbury a, 2024	prospective cohort	At approximately 10–14, 16–18, 22–24, 28–30, and 34–36 weeks of gestation, and within 24hours of the child’s birth, participants were interviewed by telephone about their medication use (between last and current interview), including acetaminophen as an active ingredient.	Caregivers were asked to participate in follow-ups of the study child. Those who agreed were mailed a packet of questionnaires which included the MacArthur-Bates Communicative Development Inventories (CDI) at 26.5–28.5 months, and the Speech and Language Assessment Scale (SLAS) at 36–38 months.	Singletons only; Not advanced maternal age. All models were adjusted for maternal parity, maternal education, mean perceived stress during pregnancy, and mean depression during pregnancy. Child sex was included as a potential modifier. Sensitivity analyses for: maternal alcohol use, smoking, mother’s native language, marital status, postnatal depression scores and the other parent’s education.
Ystrom or Gustavson (Gustavson 2021 - Sibling), 2017	prospective cohort	Mothers reported on medication use and the total number of days the medication was taken in questionnaires at gestational weeks 17 and 30, and 6 months after birth. The sum of number of days' acetaminophen exposure across all indications and all questionnaires was calculated for each child.	Information about Attention deficit hyperactivity disorder (ADHD) diagnoses came from the Norwegian Patient Registry (including all government-funded clinics from 2008 - Hyperkinetic disorder (F90) according to ICD10).	Children from multiple births were excluded. Sibling. Propensity scores were used to adjust for type and numbers of indication groups for acetaminophen use, child's birth year, maternal age, alcohol use during pregnancy, smoking during pregnancy, symptoms of anxiety and depression, use of acetaminophen before and after pregnancy, number of co‐medications used during pregnancy, and child's sex.
Ystrom or Gustavson (Ystrom - Population-Based), 2017	prospective cohort	Information on acetaminophen use was obtained through MoBa questionnaires, at week 18, week 30, and 6 months postpartum. The mother could name the medication taken in an open textbox and specify the exposure windows (total calculated across all exposure windows).	Information about children’s ADHD diagnosis was obtained from the Norwegian Patient Registry (NPR, coded with International Classification of Diseases, 10th Revision diagnoses of hyperkinetic disorder (F90.0, F90.1, F90.8, or F90.9)) between 2008 and 2014.	Adjusted for maternal and paternal use before pregnancy, birth year, parental ADHD symptoms, alcohol use during pregnancy, smoking during pregnancy, symptoms of anxiety and depression during pregnancy, maternal education, marital status, BMI at 17th week of gestation, maternal age, and parity.

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