Acetaminophen (Paracetamol)

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.
Andersen, 2012	Denmark 1996 - 2008	All singletons born alive in northern Denmark from January 1, 1996 to December 31, 2008.	Children exposed to maternal paracetamol prescription from 30 days before the first day of the last menstrual period and until delivery.	unexposed (general population or NOS) Children unexposed to maternal use of prescription paracetamol at any time during gestation.	976 / 196084
Andreasen, 2025	Denmark 2010 - 2012	All pregnant women residing in the municipality of Odense, Denmark, between January 2010 and December 2012 were invited to participate in the cohort during routine ultrasound examinations performed between GW 10 and 16 at Odense University Hospital.	Pregnant women who self-reported that they had used paracetamol during pregnancy (before GW14, or between GW15 and 29 or after GW28 or 30).	unexposed (general population or NOS) Pregnant women who self-reported that they had not used paracetamol during the entire pregnancy in questionnaires Q1, Q2 and Q3.	1106 / 608	Continuous outcomes such as anogenital distance, penile length, and penile width are not considered in metaPreg because, if they could be markers of endocrine disruption, there is no consensus on their clinical relevance in humans or on threshold values.
Arneja, 2020	Canada 2013 - 2017	Pregnant women > 18 years or older and <17 week of gestation receiving prenatal care at obstetrical clinics affiliated with Mount Sinai Hospital in Toronto	Pregnant women exposed to acetaminophen in the 3 months before pregnancy, in early pregnancy (in the first 12–16 weeks of pregnancy), and/or in mid–late pregnancy.	unexposed (general population or NOS) Pregnant women never exposed to acetaminophen (in the 3 months before pregnancy, early pregnancy: in the first 12–16 weeks of pregnancy, and mid–late pregnancy).	726 / 294	Authors provided 3 periods of exposure: early (12–16 weeks of pregnancy), mid–late pregnancy, and continuous user (in each of the three periods => Each trimester of exposure may have an impact on these outcomes => Use of continuous user.
Aselton, 1985	USA 1980 - 1982	All live-born infants whose mothers had been members of the plan for at least 280 days before delivery.	Infants of mother who filled one or more prescriptions for Paracetamol (without codeine) during the first trimester of pregnancy.	unexposed (general population or NOS) Infants of mother who did not fill prescriptions for Paracetamol (without codeine).	350 / 6159
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.
Broe (Controls unexposed, general pop), 2025	Denmark 2004 - 2017	All singleton livebirths in Denmark between January 1, 2004, and December 31, 2017.	Singleton livebirths whose mothers had filled a prescription for paracetamol between the first day in the last menstrual period (LMP) and the end of the first trimester (91days after LMP).	unexposed (general population or NOS) Singleton livebirths of women who did not redeem any drug prescription between 90 days prior to LMP and the end of the first trimester.	8590 / 471855	Infants with chromosomal abnormalities (ICD-10 codes Q90– Q99) were excluded from all analyses.
Broe (Controls unexposed, sick), 2025	Denmark 2004 - 2017	All singleton livebirths in Denmark between January 1, 2004, and December 31, 2017.	Singleton livebirths whose mothers had filled a prescription for paracetamol between the first day in the last menstrual period (LMP) and the end of the first trimester (91days after LMP).	unexposed, sick Singleton livebirths born to women who were treated with the individual drug of interest during the last year before pregnancy, but not during pregnancy.	8590 / 14817	Infants with chromosomal abnormalities (ICD-10 codes Q90– Q99) were excluded from all analyses.
Czeizel, 2005	Hungary 1980 - 1996	Liveborn infants that formed the control group (without malformations) in the population-based Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA).	Mothers who received paracetamol treatment (not in combination with other components) during pregnancy.	unexposed (general population or NOS) Mothers who did not receive paracetamol treatment during pregnancy.	173 / 37978	In general, daily 300–1000 mg of paracetamol was used for between 3 and 8 days with a mean of 4 days.
Dathe, 2019	Germany 2008 - 2017	Prospective case reports ascertained and archived at Embry- otox between January 2008 and December 2017.	Pregnancies exposed to systemic paracetamol in the third-trimester (may have started before or during the third trimester).	unexposed, sick Pregnancies exposed to systemic paracetamol in the first and/or second trimester only, but not in the third trimester.	604 / 1192	Outcomes that may result from exposure during the first and/or second trimester are not reported here (i.e stillbirths, oligohydramnios, primary pulmonary hypertension, renal disorder). Patent ductus arterious not reported (preterm births).
De Castro, 2022	Brazil 2012 - 2014	Pregnant women of any gestational age from the urban area who received prenatal care in the health clinics of the Brazilian Health System (SUS) in Santo Antonio de Jesus from June 2012 to February 2014.	Pregnant women who had taken paracetamol at some time during pregnancy.	unexposed (general population or NOS) Pregnant women who had not taken paracetamol during pregnancy.	106 / 654
Fisher, 2016	United Kingdom 2001 - 2009	Pregnant women at ~12 post-menstrual weeks of gestation from a single UK maternity unit between 2001 and 2009, and 24 months of infant follow-up.	Exposed to paracetamol at any time during pregnancy or during the masculinisation programming window (MPW, 8–14 weeks of gestation).	unexposed (general population or NOS) Not exposed to paracetamol at any time during pregnancy.	465 / 840	Continuous outcomes such as anogenital distance, penile length, and penile width are not considered in metaPreg because, if they could be markers of endocrine disruption, there is no consensus on their clinical relevance in humans or on threshold values.
Garcia-Marcos, 2009	Spain Not specified.	Preschool children from the three main cities of the province of Murcia (Murcia, Cartagena and Lorca), in the south-east of Spain.	Children whose mother having taken paracetamol during pregnancy.	unexposed (general population or NOS) Children whose mother never having taken paracetamol during pregnancy.	717 / 806	Number of exposed and unexposed: calculated based on table 1.
Goksor, 2011	Sweden 2003	Children born in the region of western Sweden in 2003.	Prenatal paracetamol exposure.	unexposed (general population or NOS) No prenatal paracetamol exposure.	334 / 4017
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.
Jedrychowski, 2011	Poland 2001 - 2004	Women attending ambulatory prenatal clinics in the first and second trimesters of pregnancy, in Krakow inner city area, who gave birth to term babies and completed 5-year follow-up.	Prenatal intake of paracetamol whenever in pregnancy irrespective of dose.	unexposed (general population or NOS) No prenatal intake of paracetamol in pregnancy.	73 / 249	Paracetamol use: 22.7% (95%CI: 17.6 – 26.8) ever during pregnancy => 73/322. There was only a significant trend for the Paracetamol doses ever taken in pregnancy and the occurrence of eczema in children (nonparametric trend z = 2.18, p = 0.029).
Jensen, 2010	Denmark 1996 – 2002	Live-born singleton sons of mothers enrolled in the Danish National Birth Cohort during 1996 – 2002.	Prenatal self-reported use of acetaminophen during pregnancy or different trimesters of pregnancy, notably the suggested male programming window (gestational weeks 8 –14).	unexposed (general population or NOS) No acetaminophen, ibuprofen, or acetylsalicylic acid exposure at any time during pregnancy.	22449 / 21504	Cryptorchidism: Overlapping between Rebordosa 2008 and Jensen 2010 => use of Jensen 2010 => Jensen 2010 designed specifically to examine cryptorchidism and included more cases (also included nonsyndromic cryptorchidism).
Källén, 2003	Sweden 1995 - 2001	All infants born in Sweden during the study period. Stillbirths were included both among cases and in the population controls.	Infants exposed to Paracetamol during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Infants non-exposed to Paracetamol during pregnancy.	36626 / 577730	No result presented for any cardiovascular defect with chromosome anomaly.
Killion, 2022	USA and Canada 2004 - 2018	Pregnant women who had a live birth, enrolled prior to 20 weeks of gestation and reported an autoimmune disorder, recruited in the USA or Canada through invitation after contacting MotherToBaby counselling, their health care provider, or internet and social media.	Pregnant women who reported an autoimmune disorder that used acetaminophen during pregnancy (or trimester 1; 2 or 3).	unexposed, sick Pregnant women who reported an autoimmune disorder with no acetaminophen use during pregnancy.	1348 / 473	Control group considered as unexposed sick, even if auto-immune disorder is not always the indication => disease could have an impact on outcomes. Authors did not provide results for exposure as a whole => use of the worst case scenario (5th quintile).
Kristensen, 2011	Denmark Not specified	Women resident in hospital referral areas, recruited consecutively during pregnancy and who met the criteria: both parents and grandparents of the unborn child should have been born and raised in Denmark with a maximum residence abroad of 3 years for the mother and 10 years for the father and grandparents.	Use of paracetamol during pregnancy (first trimester or second trimester or during pregnancy).	unexposed (general population or NOS) No use of paracetamol during pregnancy (first trimester or second trimester or during pregnancy).	233 / 257	Only the computer assisted telephone interviews as part of the Danish National Birth Cohort were used for the Danish part of the study. Overlapping: DNBC also used by Jensen 2010 (1996-2002) but unspecified period of exposure for Kristensen 2011.
Li, 2003	USA 1996 - 1998	Any women members of the Kaiser Permanente care programme that resided in the San Francisco or south San Francisco area, had a positive pregnancy test, spoke English, and intended to carry the pregnancy to term at the time of recruitment.	Use of paracetamol or preparations containing it during pregnancy (Tylenol, Tylenol Cold, Tylenol Sinus, Tylenol with codeine, Tylenol PM, Theraflu, Triaminic, Vicodin), excluding NSAID or aspirin users.	unexposed (general population or NOS) No use of paracetamol or preparations containing it during pregnancy.	172 / 762	The entry time in the study was the gestational age at the positive pregnancy test, and the median gestational age at study entry was 40 days.
Li (Controls exposed to NSAIDS), 2018	USA 2005 - 2012	Pregnant Kaiser Permanente Northern California (KPNC) members, aged 18 years old or older, recruited as soon as possible after their positive pregnancy test and resided in the participating areas in the greater San Francisco Bay Area.	Pregnant women who used acetaminophen (but no nonsteroidal antiinflammatory drugs) during pregnancy.	exposed to other treatment, sick Pregnant women who used nonsteroidal antiinflammatory drugs during pregnancy.	391 / 241	The median gestational age at recruitment was 39 days (range, 4-91 days), much earlier in pregnancy than most published studies of miscarriage.
Li (Controls unexposed, NOS), 2018	USA 2005 - 2012	Pregnant Kaiser Permanente Northern California (KPNC) members, aged 18 years old or older, recruited as soon as possible after their positive pregnancy test and resided in the participating areas in the greater San Francisco Bay Area.	Pregnant women who used acetaminophen (but no nonsteroidal antiinflammatory drugs) during pregnancy.	unexposed (general population or NOS) Pregnant women who used neither nonsteroidal antiinflammatory drugs nor acetaminophen during pregnancy.	391 / 465	The median gestational age at recruitment was 39 days (range, 4-91 days), much earlier in pregnancy than most published studies of miscarriage.
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, 2021	USA Jan 2003 - Dec 2003	All singleton births from 1 January 2003 to 31 December 2003, born to mothers who resided in 111 Los Angeles County ZIP codes.	Children born to mothers who ever used acetaminophen during pregnancy.	unexposed (general population or NOS) Children born to mothers who never used acetaminophen during pregnancy.	393 / 808	Use of results of Table S1 (Model C of adjustment).
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).
Liew c, 2016	Denmark 1996 - 2002	Singleton live-born of pregnancies enrolled at the first general practitioner antenatal visit (during weeks 6 to 12).	Children born to mothers who used paracetamol during pregnancy.	unexposed (general population or NOS) Children born to mothers who never used paracetamol during pregnancy.	881 / 610	For ADHDrisk: SubAttention/hyperactivity studied by Liew 2016a,c also studied by Inoue 2021 (same dataset) => use of Inoue 2021 because older children and full cohort. Continuous outcomes also available.
Liew_Boys, 2019	Denmark 1996 - 2002	Pregnant women recruited between 6 and 12 weeks gestation from 1996 to 2002 by about 50% of all general practitioners in Denmark. Among all pregnant women invited, 60% agreed to participate.	Pregnant women with acetaminophen intake during pregnancy (stratified analysis among boys).	unexposed (general population or NOS) Pregnant women without acetaminophen intake during pregnancy (stratified analysis among boys).	8582 / 7037
Liew_Girls, 2019	Denmark 1996 - 2002	Pregnant women recruited between 6 and 12 weeks gestation from 1996 to 2002 by about 50% of all general practitioners in Denmark. Among all pregnant women invited, 60% agreed to participate.	Pregnant women with acetaminophen intake during pregnancy (stratified analysis among girls).	unexposed (general population or NOS) Pregnant women without acetaminophen intake during pregnancy (stratified analysis among girls).	8062 / 6446	Mothers who used acetaminophen for more than 30 weeks of gestation (< 2%) were excluded in linear trend tests to evaluate the influence of extreme values.
Magnus (Controls exposed to ibuprofen), 2016	Norway 1999 - 2008	Pregnant women recruited between 1999 and 2008, at approximately 18 weeks of gestation.	Prenatal exposure to paracetamol (without ibuprofen).	exposed to other treatment, sick Prenatal exposure to ibuprofen (without paracetamol).	22675 / 766
Magnus (Controls unexposed, NOS), 2016	Norway 1999 - 2008	Pregnant women recruited between 1999 and 2008, at approximately 18 weeks of gestation.	Prenatal exposure to paracetamol (and no exposure during infancy).	unexposed (general population or NOS) No prenatal or infant exposure to paracetamol.	14837 / 19912
Marild, 2017	Norway 1999 - 2008	Pregnant women recruited across Norway in the years 1999 to 2008 (41% of eligible women participated).	Any use of paracetamol during pregnancy, irrespective of the indication for use.	unexposed (general population or NOS) No use of paracetamol during pregnancy.	39117 / 45157
Okubo (Controls unexposed, general population), 2025	Japan 2005 - 2022	Mothers (182,830) who gave birth between April 2005 and March 2022 and had complete records for both the pregnancy periods and 1-year look-back periods.	Ever-use of acetaminophen during pregnancy.	unexposed (general population or NOS) No use of acetaminophen during pregnancy.	85853 / 131749	The results of the Propensity Score-matched population are reported here (main analyses). Of note: results slightly different between text and table 2 => data of the table 2 are reported here, because Supplemental Table 6 provided same values.
Okubo (Controls unexposed, sibling), 2025	Japan 2005 - 2022	Siblings of mothers who gave birth between April 2005 and March 2022 and had complete records for both the pregnancy periods and 1-year look-back periods.	Sibling children who had discordant pairs of maternal acetaminophen use: ever-use of acetaminophen during pregnancy.	sibling Sibling children who had discordant pairs of maternal acetaminophen use: no-use of acetaminophen during pregnancy.	11696 / 11897	Identification of 23,593 children who had discordant pairs of maternal acetaminophen use.
Persky, 2008	USA Not specified.	Pregnant women at risk for having children with asthma (defined as the unborn child having a first-degree relative with asthma, hay fever, or eczema), participating to the Peer Education in Pregnancy Study.	Acetaminophen use during pregnancy.	unexposed (general population or NOS) No acetaminophen use during pregnancy.	240 / 103	Ancillary study in a clinical trial, the objective of which was not the study on paracetamol at the start => considered a retrospective study. A total of 70% of women had used acetaminophen at least once in pregnancy => 240/343.
Perzanowski, 2010	USA 1998 - 2006	Expectant mothers self-reporting as being of African-American race or of Dominican Republic origin living in Northern Manhattan and the South Bronx recruited from a prenatal clinic system to participate in a birth cohort study.	Mothers that reported acetaminophen use during pregnancy.	unexposed (general population or NOS) Mothers that did not report acetaminophen use during pregnancy.	103 / 198	The frequency of prenatal exposure to acetaminophen also predicted seroatopy (Child had specific IgE (>0.35 IU/ml) to at least one allergen tested: dust mite (Dermatophagoides farinae), cockroach, mouse, cat or dog) at age 5 years.
Petersen, 2018	Denmark and Norway 1996 - 2008	Pregnant women were recruited to Danish National Birth Cohort (DNBC) in 1996–2002 around gestational week (gw) 6–12, and to Norwegian Mother and Child Cohort Study (MoBa) in 1999–2008 around gw 17–18.	Pregnant women ever exposed to paracetamol in pregnancy (or specific trimesters).	unexposed (general population or NOS) Pregnant women never exposed to paracetamol in pregnancy (or specific trimesters).	91015 / 71345
Pleau, 2025	Canada 1998 - 2015	All singleton live births between January 1, 1998, and December 31, 2013, whose mothers were covered by the RAMQ drug insurance plan for at least one month before and during pregnancy.	Children exposed to acetaminophen, i.e their mother filled at least one prescription of acetaminophen during the second or third trimester of pregnancy or if a prescription overlapped with the start of the second trimester.	unexposed (general population or NOS) No acetaminophen prescription during the second or third trimester (and mainly unexposed during the 1st trimester).	1827 / 176993	Results of 'Acetaminophen alone' were reported rather than 'Acetaminophen in combination'. Moreover, unexposed group mainly (>98%) not exposed during pregnancy (and adjusted for 'acetaminophen use during the first trimester') => Considered as unexposed.
Rebordosa, 2009	Denmark 1996 - 2003	Pregnant women invited to participate in the Danish National Birth Cohort between 1996 and 2003.	Use of acetaminophen during pregnancy (or in specific trimester).	unexposed (general population or NOS) No use of acetaminophen during pregnancy (or for each specific trimester, irrespective of drug use during the other trimesters).	50702 / 47438	Women who delivered live born children reported having used acetaminophen on average 9.4 weeks during pregnancy.
Rebordosa, 2010	Denmark 1996 - 2003	Pregnant women who gave birth to a live born singleton approached by their general practitioner during their first antenatal visit that took place between the 6th and the 12th gestational weeks.	Pregnant women who used acetaminophen during pregnancy (ever, 1st, 2nd, 3rd trimester).	unexposed (general population or NOS) Pregnant women who did not take acetaminophen during the trimester of interest or whether they used it in other trimesters or not. For ever users, the reference group were women who did not use the drug during the whole pregnancy.	35992 / 27841	Dose-response relationship provided only for Acetaminophen use during the third trimester of pregnancy (not provided for 1st trimester).
Rebordosa a, 2008	Denmark 1996 - 2003	Pregnant women and their live-born singletons from the Danish National Birth Cohort, approached at the first prenatal care visit to a general practitioner, which usually took place after 6-10 weeks of gestation.	Children exposed to acetaminophen during the first trimester of pregnancy (including acetaminophen alone or in combination, including both over-the-counter and prescribed drugs).	unexposed (general population or NOS) Children nonexposed to acetaminophen during the first trimester of pregnancy.	26424 / 61718	Cryptorchidism: Overlapping between Rebordosa 2008 and Jensen 2010 => use of Jensen 2010 => Jensen 2010 designed specifically to examine cryptorchidism and included more cases (also included nonsyndromic cryptorchidism).
Rebordosa b, 2008	Denmark 1996 - 2003	Women who gave birth to a singleton between 1996 and 2003 and provided information on paracetamol use during pregnancy.	Women who gave birth to a singleton and use paracetamol during pregnancy (ever, 1st, 2nd, 3rd trimester).	unexposed (general population or NOS) Women who gave birth to a singleton and did not use paracetamol during pregnancy (ever, 1st, 2nd, 3rd trimester).	49029 / 41430	Overlapping between Liu 2016 and Rebordosa 2008 => Use of Rebordosa 2008 because more exposed pregnancy, results with longer follow up and better adjustment for confusion.
Rifas-Shiman, 2020	USA 1999 - 2002	Women who delivered a live singleton infant, recruited in early pregnancy into Project Viva from 8 obstetric offices.	Pregnant women reporting use of acetaminophen during pregnancy.	unexposed (general population or NOS) Pregnant women that did not report use of acetaminophen during pregnancy.	855 / 370	Authors assessed category of acetaminophen intake during pregnancy: never; 5 times; 10 times or >=15 times. => Use of the data the maximalist data (i.e >=15 times). OR based on mean, sd and n. Use of parents-reported outcome.
Rumack, 1981	USA Not specified.	108 premature infants born at or before 34 weeks' gestation or who weighed 1500g or less at birth in the participating level 3 neonatal intensive care nurseries.	Infants whose mothers took 1 or more acetaminophen tablets within 1 week of delivery.	unexposed (general population or NOS) Infants whose mothers took neither aspirin nor acetaminophen during the week prior to delivery.	20 / 71
Shaheen (Controls unexposed, general pop), 2019	Sweden 2005 - 2010	All children born to women who became pregnant from July 2005 onwards and gave birth before the end of 2010 (>98% of all births in Sweden).	Children born to women who were prescribed paracetamol during pregnancy.	unexposed (general population or NOS) Children born to women who were not prescribed paracetamol during pregnancy.	14732 / 478267	Authors provided results at age 2, 3, 4, 5 and 6 years => Use of results of infants of 6 years old because 'asthma' in those aged <4.5 years of age may actually be pre-school wheezing that will not persist as asthma later in childhood.
Shaheen (Controls unexposed, sibling), 2019	Sweden 2005 - 2010	All children born to women who became pregnant from July 2005 onwards and gave birth before the end of 2010 (>98% of all births in Sweden).	Sibling children born to women who were prescribed paracetamol during pregnancy.	sibling Discordant sibling children born to women who were not prescribed paracetamol during pregnancy.	-9 / -9	Authors provided results at age 2, 3, 4 => Use of results of infants of 4 years old because 'asthma' in those aged <4.5 years of age may actually be pre-school wheezing that will not persist as asthma later in childhood.
Smith-Webb, 2023	United States and Canada 1996 - 2002	Singleton control children, without a major malformation, with data on maternal exposures and neurodevelopment assessments in both childhood and adolescence, randomly selected from the same birth population as cases of hemifacial microsomia and matched on birth year, pediatric practice, or practices within the same zip code.	Children of mothers that reported any medication that contained acetaminophen alone or in combination with other medications during pregnancy.	unexposed (general population or NOS) Children of mothers reporting no acetaminophen during pregnancy.	143 / 73	Overlapping with Parker 2020 that used same dataset for assess the same outcomes, at a younger age => use of Smith-Webb 2023. Use of parents-reported outcomes.
Snijder, 2012	The Netherlands 2002 - 2006	All pregnant women who had an expected delivery date between April 2002 and January 2006 and who lived in the study area of Rotterdam were invited to participate.	Pregnant women who who used acetaminophen during the periconception period (use before and during the first trimester of pregnancy), or during the first period (first 14 weeks of gestation), or during the second period (14–22 weeks of gestation) or during the third period (20–32 weeks of gestation).	unexposed (general population or NOS) Pregnant women who did not use any medication during pregnancy.	-9 / -9	When cryptorchidism or hypospadia was present at one of the 10 visits to the child health care centres, children were classified as a prevalent case => cumulative period prevalence of cryptorchidism and hypospadia over 30 months of follow up.
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
Tapia, 2018	Norway 1999 - 2008	Live-born children who survived their first year of life whose mothers were recruited around pregnancy week 17 during 1999–2008.	Acetaminophen exposure in pregnancy.	unexposed (general population or NOS) No acetaminophen exposure in pregnancy.	-9 / -9	Number of exposures and non exposures not provided by authors.
Thulstrup, 1999	Denmark 1991 - 1996	All pregnant women of the County of North Jutland (about 9% of the Danish population) who gave birth to a single child during the study period.	Pregnant women who had received a prescription of acetaminophen during pregnancy and/or 30 days before conception.	unexposed (general population or NOS) Pregnant women who did not received any prescription at all 30 days before conception or during pregnancy.	123 / 13329
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).
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).
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 maximalist duration (i.e 3 trimesters).
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 maximalist duration (i.e >= 28 days). Use of motor milestone outcome.
Walker, 2024	New Zealand 2009 - 2010	Women recruited during pregnancy across the wider Auckland and Waikato districts, New Zealand.	Mothers who reported having taken paracetamol at some timepoints during pregnancy (during the first three months or after the first three months of pregnancy).	unexposed (general population or NOS) Mothers who did not reporte having taken paracetamol during pregnancy (neither during the first three months nor after the first three months of pregnancy).	1602 / 1401	OR based on R package 'compute.es'. Authors assessed category of acetaminophen intake during pregnancy: never; some timepoints; both timepoints => Use of the data the maximalist one (i.e both timepoints).
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.
Xu, 2024	China 2018 - 2023	Pregnant women who delivered in the Beijing Obstetrics and Gynecology Hospital from January 2018 to September 2023.	Pregnant women who had been exposed to acetaminophen during pregnancy, regardless of the dosage and course of the treatment.	unexposed (general population or NOS) Pregnant women who had not been exposed to acetaminophen or any other medication during pregnancy.	501 / 501
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 maximalist duration (i.e >= 29 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.
Zafeiri, 2022	Scotland 1985 - 2015	Singleton pregnancies spanning three decades of population-based data from a single maternity hospital serving the entire population of Aberdeenshire in the Northeast of Scotland.	Consumption of Paracetamol only (among analgesic) during pregnancy.	unexposed (general population or NOS) No analgesic consumption (paracetamol, ibuprofen, naproxen, diclofenac or aspirin) during pregnancy.	24099 / 107143

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
Cifuentes, 2025	Europe (13 countries) 1995 - 2019	Registrants (liveborn, stillborn, or induced terminations) with congenital ocular anomalies (COA).	Registrants with major congenital anomalies (excluding genetic syndromes) other than congenital ocular anomalies (COA) and nervous system anomalies (except spina bifida) as central nervous system development is closely linked to eye development.	4185 / 232718	Use of nongenetic controls (cases of congenital anomalies other than congenital ocular anomalies excluding genetic syndromes).
Couto, 2015	Brazil 1999 - 2007	Children with a diagnosis of acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) by morphological and immunophenotypical methods before the age of 2 years.	Children in the same age range who were hospitalized at the same hospitals as the cases or at general hospitals located in the same municipality from which the cases originated and who were undergoing medical treatment for nonmalignant diseases.	231 / 411	Results during each trimester not indexed because unexposed control group can be exposed during other trimesters of pregnancy (1st; 2nd; 3rd trimesters were not mutually exclusive).
Feldkamp, 2010	USA 1997 - 2004	Live births, stillbirths, and pregnancy terminations with selected birth defects identified through population-based birth-defect registries.	Live births without birth defects selected randomly from all live births to represent the case population of each center.	11610 / 4500	Overlapping: Feldkamp 2010 (1997-2004), Lind 2013 (1997-2007), Cleves 2004 (1997-1998), Weber 2019 (1997-2011; 1 study site); Mac Bird 2009 (during pregnancy) => Use of Feldkamp 2010 and Lind 2013 (hypospadias): more cases and 1st Trimester exposure.
Given, 2017	14: Belgium, Croatia, Denmark, FR, Germany, Ireland, Italy, Netherlands, Norway, Ukraine, UK... 1995 - 2012	Infants with gastroschisis (ICD-9 with BPA extension code 75671 or ICD-10 code Q793).	Infants with a diagnosis of a major congenital anomaly not including gastroschisis.	1587 / 154877	Medications taken in the second or third trimester or where the timing was unknown were excluded.
Goodman, 2019	USA 2010 - 2012	Singleton pregnancies with a diagnosis of isolated fetal gastroschisis by ultrasound less than 24 weeks gestation, confirmed by a Maternal-Fetal Medicine physician.	Patients who were referred for routine second trimester anatomy ultrasounds and who had a singleton with normal ultrasound.	30 / 76	Women with multiple pregnancies or a fetus known to have lethal anomalies, and/or chromosome abnormalities were excluded.
Kerr, 2019	USA and Canada 1993 - 2015	Infants with microcephaly alone (“isolated”) and microcephaly that included other major birth defects (“non-isolated”),	Nonmalformed live-born infants.	166 / 12059	Authors analyzed separately 'isolated' microcephaly and 'non-isolated' microcephaly. Only isolated microcephaly are indexed in MetaPreg.
Koniman, 2007	Singapore 2005 - 2006	Child between 3 and 10 year of age, with allergic asthma (i.e active asthma and doctor-diagnosed asthma).	Sibling child between 3 and 10 year of age, without asthma, rhinitis and eczema (i.e no symptoms of asthma, wheezing, rhinitis, eczema, urticaria and angioedema either at present or in the past).	38 / 42
Li, 2021	Taiwan 1998 - 2008	Children who received diagnoses of Atopic dermatitis (AD) (ICD-9-CM code: 691.8) by board-certified dermatologist at least twice were identified and linked with their mothers (mother-child-with-AD pairs).	Children who did not received diagnoses of Atopic dermatitis (AD) randomly (1:2) selected after matching for the mothers’ age, children's sex and age, pregnant age of mothers, income, and urbanization level.	2529 / 5058
Lind, 2013	USA 1997 - 2007	Male infants with isolated second- or third-degree hypospadias, defined as the urethral opening at the penile shaft, scrotum, or perineum.	Male infants with no major birth defects selected randomly from vital records or birth logs.	1537 / 4314	For hypospadias: Overlapping between Lind 2013 (1997 - 2007) and Feldkamp 2010 (1997 - 2004) with more cases in Lind 2103 => The MA only included hypospadias data of Lind 2013.
Malaeb, 2021	Lebanon Jan - Sep 2017	Children diagnosed asthma with symptoms (chronic wheezing, cough, and dyspnea), and an affirmative answer to the question 'did your doctor ever tell you that your child has asthma?' .	Children with neither a physician-diagnosed respiratory illness nor respiratory symptoms (wheezing, coughing, and dyspnea).	107 / 893	Children were excluded from the analysis if they had respiratory symptoms without a physician’s diagnosis of asthma. Logistic regression results provided only for Paracetamol intake during pregnancy once per week.
Nelson, 1971	United Kingdom 2 years period (NOS)	Mothers that gave birth to infants with congenital abnormalities.	Mothers of the next normal babies born after the congenitally abnormal ones in the same maternity units and mothers of normal babies matched in respect of maternal age and parity and babies' sex with a similar number in the study group.	478 / 911
Ognjanovic, 2011	Canada, USA 1996 - 2006	Infants diagnosed with or treated for acute lymphoblastic leukaemias (ALL) or acute myeloid leukaemias (AML) in the first year of life.	Controls identified using random digit dialling or through a sample of state birth registries.	434 / 323
Pastore, 1999	USA Year 1984	Stillbirths (fetal deaths after 20 weeks' gestation) and infant deaths within 24 h of birth.	Randomly selected live births born in the same year and matched by maternal age and county of maternal residence.	332 / 357	Deaths occurring within 24 h of birth were included because many deaths that occur within minutes or hours after birth share aetiology with those born dead and, in the absence of medical intervention, would have been stillborn.
Pérez-Molina, 2002	Mexico 1989 - 1997	All newborns (live or stillborn) diagnosed with high or low neural tube defects (NTDs).	Newborns selected as the next birth following each malformed newborn, of the same sex, but without any external congenital malformation.	166 / 166	Newborns with Meckel–Gruber syndrome, amniotic bands, partial duplication of chromosome 11q, or trisomy 13 or 18 were excluded. Data only provided for high Neural tube defects (NTDs) => considered as Neural tube defects subgroup of malformations.
Poletta, 2012	South America 1967 - 2008	Infants with any of the birth defects (alone or in combination with other birth defects) (excluding cases with aetiologic syndromes and hose with only a minor birth defect).	Non-malformed newborns registered by the Latin American Collaborative Study of Congenital Anomalies (ECLAMC) in the same hospital and period.	58514 / 110814	Only malformations as a whole reported here (OR not provided but raw data provided by authors). Individual malformations not reported here because authors provided 99% CI (raw data not provided to calculate the 95% CI).
Puho, 2007	Hungary 1980 - 1996	Cases with isolated cleft lip with or without cleft palate (CL/P) and posterior cleft palate (PCP).	Newborn infants without congenital abnormalities	1975 / 38151
Robledo-Aceves, 2015	Mexico 2009 - 2013	Newborns with nonsyndromic gastroschisis, confirmed by the surgical description of the defect, reviewed by clinical geneticists for confirmation.	Newborns without major external congenital anomalies, matched for gender and who were randomly selected from all infants born alive in the hospital.	90 / 180
Ross, 2003	USA and Canada 1983 - 1988	Children diagnosed with acute leukemia (i.e., acute myeloid leukemia, AML and acute lymphoblastic leukemia, ALL) in the first 18 months of life.	Children without leukemia identified through random digit dialing.	243 / 393
Torfs, 1996	USA 1989 - 1990	Singleton infants born with gastroschisis (diagnosis reviewed by a pediatric geneticist).	Singleton infants without a clinically detected structural birth defect, randomly selected from the birth certificate records of the California Department of Vital Statistics in the counties surveyed by CBDMP.	110 / 220
Werler, 1992	USA 1976 - 1990	Infants with gastroschisis.	Infants with malformations other than gastroschisis, other defects thought to have a possible vascular etiology or chromosomal anomalies.	76 / 2142	No overlapping between Werler 1992 (1976-1990) and Werler 2002 (1995 - 1999).
Werler, 2002	USA and Canada 1995 - 1999	Newborn infants with gastroschisis or Small intestinal atresia (SIA).	Infants with major structural malformations other than gastroschisis, SIA, or other gastrointestinal defects and infants with medical conditions requiring hospital admission (but no malformations).	332 / 798	No overlapping between Werler 1992 (1976-1990) and Werler 2002 (1995 - 1999). Single use preferred at acetaminophen in combination.
Werler, 2014	USA 2007 - 2011	All infants less than 11 months of age with a diagnosis of talipes equinovarus or clubfoot (without a known chromosomal anomaly, inherited syndrome, bilateral renal agenesis, Potter syndrome, or neural tube defect).	Random samples of children born in the same years as cases but without known malformations.	646 / 2037	'On the basis of the timing of clubfoot development, the exposure window of interest is lunar months (LMs) 2–4, which is 29–112 days after the first day of the last menstrual period.'
Werler, 2003	USA 1976 - 1998	Infants (or fetuses from 1989) with the diagnosis of amniotic rupture sequence or body wall complex.	Infants (or fetuses from 1989) with other major malformations (exclusion of infants with oral clefts, anophthalmia, microphthalmia, or defects of limb reduction, the abdominal wall, or the neural tube).	84 / 12227	Addition of the 3 subgroups of malformations (ARS-L, ARS-NL and BWC) that are included in the Amniotic Band Defects (loss of the adjustment, which was not complete anyway).
Winship, 1984	United Kingdom Jan 1981 - Dec 1981	Child (liveborn and stillborn) with actual or suspected defects, notified at the Committee on Safety of Medicines (CSM).	Liveborn child without a congenital abnormality from the same medical practice.	764 / 764
Zarante, 2009	Colombia 2001- 2006	All newborns and stillborns of weight >500 g that presented only one craniofacial malformation, not associated with any other congenital condition.	The next non-malformed same sex child born in the same hospital.	374 / 728
Zierler, 1985	United States 1980 - 1983	Infants born alive with severe congenital heart disease (cardiac catheterization or surgery or death within the first year of life).	Infants randomly selected from all available birth certificates, without congenital heart disease.	298 / 738	The authors provided a 90% confidence interval, without adjustment => here a 95% confidence interval was calculated to be homogeneous with other studies.

master protocol