Acetaminophen (Neuro-developmental outcomes)

Exposed non-exposed, cohort studies

Study Country
Study period
Study design		 Data source Exposure definition Non-exposure definition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Ahlqvist (Population-Based)
2024 		Sweden
1995 - 2019
population based cohort retrospective 		The Swedish Medical Birth Register, the Prescribed Drug Register and the National Patient Register. Children exposed to acetaminophen (ATC: N02BE) during pregnancy (ever-use). unexposed (general population or NOS)
Children not exposed to acetaminophen (ATC: N02BE) during pregnancy. 		during pregnancy (anytime or not specified) 185909 / 2294888
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.
Ahlqvist (Sibling)
2024 		Sweden
1995 - 2019
population based cohort retrospective 		The Swedish Medical Birth Register, the Prescribed Drug Register and the National Patient Register. Sibling cohort: Offspring of pregnant individuals who had discordant acetaminophen (ATC: N02BE) use across pregnancies, and with use of acetaminophen during pregnancies. sibling
Sibling cohort: Offspring of pregnant individuals who had discordant acetaminophen (ATC: N02BE) use across pregnancies, and no use of acetaminophen during pregnancies. 		during pregnancy (anytime or not specified) -9 / -9 Results of the Sibling cohort reported here. Number of offsprings in each group of exposure not provided.
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.
Alemany_DNBC
2021 		Denmark
1996 - 2002
prospective cohort 		The Danish National Birth Cohort (DNBC). Mothers that used acetaminophen during pregnancy at any dose and at any time up during pregnancy. unexposed (general population or NOS)
Mothers that did not use acetaminophen during pregnancy. 		during pregnancy (anytime or not specified) 34584 / 26846 For ADHD and ASDdiag: Overlapping: original data published by Liew 2014; Inoue 2021 ans Liew 2016b=> not reported here; but ASDrisk outcome reported here because not provided in other studies.
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.
Bertoldi_Pelotas
2020 		Brazil
Jan - Dec 2015
prospective cohort 		The 2015 Pelotas Birth Cohort in southern Brazil. Any use of acetaminophen in 1st, 2nd, and/or 3rd trim rimester of pregnancy. unexposed (general population or NOS)
No use of acetaminophen in 1st, 2nd, and/or 3rd trim rimester of pregnancy. 		, 1st and 2nd trimester, during pregnancy (anytime or not specified), throughout pregnancy 2470 / 1348 Bêtas are reported. OR were calculated based on mean, sd and n. Women recruited prenatally (before 16 weeks of gestation) and perinatal (hours after delivery). => 73.8% of the mothers enrolled prenatally. => Considered as 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.
Inoue
2021 		Denmark
1996 - 2002
prospective cohort 		The Danish National Birth Cohort Children of mothers that reported use of acetaminophen at least once during pregnancy. unexposed (general population or NOS)
Children of mothers that did not report use of acetaminophen during pregnancy. 		1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified), throughout pregnancy 21670 / 19264 Overlapping: for ADHD risk => use of the same dataset and same tool (SDQ) than data in Alemany 2024 (younger children) => use of Inoue 2021. Use of parents-reported outcome adjusted for parents’ behavioral problems in childhood.
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.
Liew
2014 		Denmark
1996 - 2002
prospective cohort 		The Lifestyle During Pregnancy Study (LDPS), a sub-cohort nested within the Danish National Birth Cohort (DNBC), combined with the Danish National Hospital Registry, the Danish Psychiatric Central Registry and the Danish Prescription Registry. Children born to mothers who reported use of acetaminophen during the entire pregnancy or during the first (1-12 weeks), second (13-24 weeks), or third (25th-delivery) trimester. unexposed (general population or NOS)
Children born to mothers who never used acetaminophen during pregnancy or the reported period of exposure. 		, 1st and 2nd trimester, 1st trimester, 2nd and/or 3rd trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified), throughout pregnancy 36187 / 28135 Methods completed with Liew 2016. Overlapping: For ADHD: Liew 2016a studied Attention and Liew 2014 studies ADHD medication or hyperkinetic disorder (with same dataset) => only 1 result reported: the most global and robust: i.e Liew 2014 (ICD-10).
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.
Liew a
2016 		Denmark
1996 - 2002
prospective cohort 		The Lifestyle During Pregnancy Study (LDPS), a sub-cohort nested within the Danish National Birth Cohort (DNBC), combined with the Danish National Hospital Registry and the Danish Psychiatric Central Registry. Children born to mothers who used acetaminophen during pregnancy (ever use, trimester of use, and total weeks of use). unexposed (general population or NOS)
Children born to mothers who never used acetaminophen during pregnancy. 		during pregnancy (anytime or not specified) 881 / 610 Authors provided: Mean Difference (95% CI). OR based on R package 'compute.es'. Methods completed with Liew 2016a, b and c.
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.
Liew b
2016 		Denmark
1996 - 2002
prospective cohort 		The Lifestyle During Pregnancy Study (LDPS), a sub-cohort nested within the Danish National Birth Cohort (DNBC), combined with the Danish National Hospital Registry and the Danish Psychiatric Central Registry. Children of women with maternal acetaminophen use during pregnancy. unexposed (general population or NOS)
Children of women who did not use acetaminophen while pregnant. 		, 1st and 2nd trimester, 1st trimester, 2nd and/or 3rd trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified), throughout pregnancy 36187 / 28135 Methods completed with Liew 2016a, b and c. Data on Asperger syndrome (F84.5), and Pervasive Developmental Disorder not otherwise specified (PDD-NOS) not reported here because only provided by subgroup (with or without hyperkinetic disorder).
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.
Sznajder
2022 		USA
2009 - 2011
prospective cohort 		The First Baby Study, a prospective cohort study conducted in Pennsylvania, USA. Pregnant women who reported using acetaminophen during pregnancy. unexposed (general population or NOS)
Pregnant women who did not report using acetaminophen during pregnancy. 		during pregnancy (anytime or not specified) 1011 / 1411
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.
Tovo-Rodrigues
2020 		Brazil
Jan - Dec 2004
prospective cohort 		A prospective longitudinal population-based study using data from the 2004 Pelotas birth cohort, Pelotas, southern Brazil. Mothers that use acetaminophen at least once during pregnancy, regardless of the dose used. unexposed (general population or NOS)
Mothers that did not use acetaminophen during pregnancy. 		during pregnancy (anytime or not specified) 1060 / -9 N0 ?. For Emotional, behavioral and ADHD: Overlapping between Tovo-Rodriguez 2018 and 2020 (same population, same outcomes, 2 different tools and different ages), use of Tovo-Rodriguez 2018 because older children (6-11 years compared with 48 months).
Maternal use of medication during pregnancy was retrospectively assessed using a standardised questionnaire applied at the perinatal evaluation (within 24 hours after delivery).
Tovo-Rodrigues
2018 		Brazil
Jan - Dec 2004
prospective cohort 		A prospective longitudinal population-based study using data from the 2004 Pelotas birth cohort, Pelotas, southern Brazil. Mothers that was used medication composed of acetaminophen at least once during pregnancy. unexposed (general population or NOS)
Mothers that did not use medication composed of acetaminophen during pregnancy. 		during pregnancy (anytime or not specified) 965 / 2505 N1/N0 at 6 years. For Emotional, behavioral and ADHD: Overlapping between Tovo-Rodriguez 2018 and 2020 (same population, same outcomes, 2 different tools and different ages), use of Tovo-Rodriguez 2018 because older children (6-11 years versus 48 months).
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.
Tronnes
2020 		Norway
1999 - 2008
prospective cohort 		A sub‐study of the Norwegian Mother and Child Cohort Study (MoBa), linked with the Medical Birth Registry of Norway. Mothers who had used paracetamol at least once during the pregnancy (in one trimester, in two trimesters or in three trimesters). unexposed (general population or NOS)
Mothers who did not use paracetamol during pregnancy (mutually exclusive groups). 		during pregnancy (anytime or not specified) 15126 / 17808 Authors provided 3 durations of use: in 1 trimester; in 2 trimesters; in 3 trimesters (without global analysis of whole exposure) => use of the duration more comparable with other studies and more pregnancies (i.e in 1 trimester).
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.
Vlenterie
2016 		Norway
1999 - 2008
prospective cohort 		The Norwegian Mother and Child Cohort Study (MoBa), linked with the Medical Birth Registry of Norway. Infants with in utero paracetamol exposure: short-term exposure (1–27 days) or long-term exposure (28 days or more). unexposed (general population or NOS)
Infants without in utero paracetamol exposure. 		during pregnancy (anytime or not specified) 20749 / 30451 Non motor outcomes: Overlapping: same dataset, outcomes and tools than in Tronnes 2020 (older children) => use of Tronnes. 2 durations of use provided: use of the duration more comparable with other studies (i.e < 28 days). Use of motor milestone outcome.
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).
Woodbury a
2024 		USA
2013 - 2020
prospective cohort 		The Illinois Kids Development Study (IKIDS), a prospective birth cohort, USA. Participants that took acetaminophen during pregnancy. unexposed (general population or NOS)
Participants that did not take acetaminophen during pregnancy. 		1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) 377 / 155 Results of the Speech and Language Assessment Scale at 3 years not reported here because provided as continuous values. Use of Expressive vocabulary, because: use in the short version of the MBCDI and other scales mostly measure expressive vocabulary.
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.
Ystrom or Gustavson (Gustavson 2021 - Sibling)
2017 		Norway
1999 - 2008
prospective cohort 		The prospective Norwegian Mother, Father, and Child Cohort Study (MoBa). Sibling children exposed to Acetaminophen (ATC code N02BE01) during pregnancy. sibling
Sibling children not exposed to Acetaminophen (ATC code N02BE01) during pregnancy. 		during pregnancy (anytime or not specified) 7988 / 15165 Authors provided 3 durations of use: 1-7 days; 8-28 days; >= 29 days (without global analysis of whole exposure) => use of the duration more comparable with other studies and more pregnancies (i.e 1-7 days).
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.
Ystrom or Gustavson (Ystrom - Population-Based)
2017 		Norway
1999 - 2009
prospective cohort 		The Norwegian Mother and Child Cohort Study (MoBa), linked with the Norwegian Patient Registry. Pregnant women that reported use of acetaminophen during pregnancy. unexposed (general population or NOS)
Pregnant women that reported never use of acetaminophen during pregnancy. 		, 1st and 2nd trimester, 1st trimester, 2nd and/or 3rd trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified), throughout pregnancy 52707 / 60266 Overlapping: Gustavson 2019 and Stoltenberg 2020 => 2 ad hoc studies (dedicated to fever indication and methodological one, respectively) essentially based on the same dataset than Ystrom 2017 (prenatal acetaminophen and ADHD) => use of Ystrom 2017.
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).

Case-control studies

Study Country
Study period
Study design		 Data source Case Control Exposition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Chen
2019 		Taiwan
1998 - 2008
nested case control 		A matched mother-child pair sample identified from the Taiwan Longitudinal Health Insurance Database. Children who received diagnoses of Attention-Deficit/Hyperactivity Disorder (ICD-9-CM code: 314) by board-certified psychiatrists on the basis of diagnostic interviews and clinical judgement. Children who did not receive diagnosis of Attention-Deficit/Hyperactivity Disorder randomly (1:4) identified on the basis of the mothers’ ages, children’s sex and ages, mothers’ age during pregnancy, income, and urbanization level. The Taiwan Longitudinal Health Insurance Database that contains comprehensive data on insured individuals, including prescriptions. 1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) 950 / 3800
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).

Risk of bias: : NA;   : low;   : moderate;   : serious;   : critical;   : unclear;  

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