Acetaminophen (Neuro-developmental outcomes) - Medication and Pregnancy KB

Acetaminophen (Neuro-developmental outcomes)

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Ahlqvist (Population-Based), 2024	Sweden 1995 - 2019	All singleton liveborn children in Sweden from July 1, 1995, to December 31, 2019, with a linkable personal identifier.	Children exposed to acetaminophen (ATC: N02BE) during pregnancy (ever-use).	unexposed (general population or NOS) Children not exposed to acetaminophen (ATC: N02BE) during pregnancy.	185909 / 2294888
Ahlqvist (Sibling), 2024	Sweden 1995 - 2019	All singleton liveborn children in Sweden from July 1, 1995, to December 31, 2019, with a linkable personal identifier.	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.	-9 / -9	Results of the Sibling cohort reported here. Number of offsprings in each group of exposure not provided.
Alemany_DNBC, 2021	Denmark 1996 - 2002	Pregnant women enrolled through their general practitioners during early gestation (weeks 6 to 12).	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.	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.
Bertoldi_Pelotas, 2020	Brazil Jan - Dec 2015	Pregnant women recruited during antenatal care (73.8%) (before 16 weeks) or for those not already enrolled: women who gave birth in any of the 5 maternity hospitals of the city of Pelotas from 1 January to 31 December 2015.	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.	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.
Inoue, 2021	Denmark 1996 - 2002	Live-born children whose mothers answered the study enrollment form and the 3 subsequent telephone interviews after to be enrolled in the cohort at their first general-practitioner antenatal visit (during weeks 6–12).	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.	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.
Liew, 2014	Denmark 1996 - 2002	Singleton live born children whose mothers participated in all three telephone interviews after being recruited through their general practitioners (about 50% of all general practitioners in Denmark participated in the study) during early gestation (weeks 6–12).	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.	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).
Liew a, 2016	Denmark 1996 - 2002	Singleton live-born of pregnancies enrolled at the first general practitioner antenatal visit (during weeks 6 to 12). The LDPS sampling was based on maternal alcohol and binge drinking reported during pregnancy (by timing and amount of consumptions) with an oversampling strategy to select the high-alcohol-exposed subgroup.	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.	881 / 610	Authors provided: Mean Difference (95% CI). OR based on R package 'compute.es'. Methods completed with Liew 2016a, b and c.
Liew b, 2016	Denmark 1996 - 2002	Singleton live born children whose mothers participated in all three telephone interviews after being recruited through their general practitioners (about 50% of all general practitioners in Denmark participated in the study) during early gestation (weeks 6–12).	Children of women with maternal acetaminophen use during pregnancy.	unexposed (general population or NOS) Children of women who did not use acetaminophen while pregnant.	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).
Sznajder, 2022	USA 2009 - 2011	Pregnant women (first pregnancy > 20 GW) age 18 to 35 at the time of recruitment, English or Spanish speaking, and planning to deliver at one of the 78 hospitals in Pennsylvania.	Pregnant women who reported using acetaminophen during pregnancy.	unexposed (general population or NOS) Pregnant women who did not report using acetaminophen during pregnancy.	1011 / 1411
Tovo-Rodrigues, 2018	Brazil Jan - Dec 2004	Mothers who living in the urban area of Pelotas or in Jardim América, 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.	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).
Tovo-Rodrigues, 2020	Brazil Jan - Dec 2004	Mothers who living in the urban area of Pelotas or in Jardim América, interviewed within 24 hours after delivery.	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.	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).
Tronnes, 2020	Norway 1999 - 2008	Pregnant women recruited in Norway between 1999 and 2008 at their routine ultrasound examination at gestational week 17‐18.	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).	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).
Vlenterie, 2016	Norway 1999 - 2008	All live-born singletons of the mothers including in the MoBa cohort, giving birth before 2009 except for infants born with major congenital malformations and infants with missing questionnaire information.	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.	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.
Woodbury a, 2024	USA 2013 - 2020	Pregnant participants, <15 weeks of gestation recruited at two local obstetric clinics and gave birth at two local hospitals, at their first prenatal visit.	Participants that took acetaminophen during pregnancy.	unexposed (general population or NOS) Participants that did not take acetaminophen during pregnancy.	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.
Ystrom or Gustavson (Gustavson 2021 - Sibling), 2017	Norway 1999 - 2008	Pregnant women from all over Norway recruited between 1999 and 2008 when they were invited to their routine ultrasound examination in gestational week 17.	Sibling children exposed to Acetaminophen (ATC code N02BE01) during pregnancy.	sibling Sibling children not exposed to Acetaminophen (ATC code N02BE01) during pregnancy.	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).
Ystrom or Gustavson (Ystrom - Population-Based), 2017	Norway 1999 - 2009	Pregnant women in Norway who consented to participate after being invited by mail in connection with the routine ultrasound examination offered at the local hospitals around pregnancy week 18.	Pregnant women that reported use of acetaminophen during pregnancy.	unexposed (general population or NOS) Pregnant women that reported never use of acetaminophen during 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.

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk
Chen, 2019	Taiwan 1998 - 2008	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.	950 / 3800

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