| 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. | ||||||||
|
Andersen 2012 |
Denmark 1996 - 2008 population based cohort retrospective |
Population-based registries in northern Denmark (the Danish Medical Birth Registry, the Danish National Health Service, the Danish National Patient Registry and the Aarhus University Prescription Database (AUPD)). | 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. |
1st trimester, 2nd and/or 3rd trimester, during pregnancy (anytime or not specified) | 976 / 196084 | ||
| Maternal by-prescription paracetamol was extracted from the Aarhus University Prescription Database (AUPD), which includes data on all reimbursed medicines dispensed at community pharmacies in northern Denmark. | ||||||||
|
Andreasen 2025 |
Denmark 2010 - 2012 prospective cohort |
The Odense Child Cohort (OCC) conducted at Odense University Hospital, Denmark. | 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. |
1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) | 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. | |
| Paracetamol exposure during pregnancy was evaluated by self-reported questionnaires on medication use during pregnancy and by measuring maternal paracetamol concentrations in urine samples. All pregnant women were asked to complete two questionnaires (Q1–2) during pregnancy and one after (Q3). | ||||||||
|
Arneja 2020 |
Canada 2013 - 2017 prospective cohort |
The Ontario Birth Study (OBS), an ongoing prospective pregnancy and birth cohort study established in Ontario, Canada. | 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). |
2nd and/or 3rd trimester, 3 months or more before pregnancy or1st trimester, throughout 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. | |
| Participants completed three self-administered comprehensive questionnaires at 12–16 weeks of gestation, 24–28 weeks of gestation, and 6–10 weeks postpartum to capture exposures, including acetaminophen. | ||||||||
|
Aselton 1985 |
USA 1980 - 1982 retrospective cohort (claims database) |
Group Health cooperative of Puget, a consumer-owned health care cooperative, Seattle, USA. | 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). |
1st trimester | 350 / 6159 | ||
| Automated pharmacy records from Seattle, giving outpatient drug and hospitalization information. | ||||||||
|
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. | ||||||||
|
Broe (Controls unexposed, general pop) 2025 |
Denmark 2004 - 2017 population based cohort retrospective |
Danish national health registries (the Danish Medical Birth registry, the Danish Civil Registration Registry, the Danish National Prescription Registry, the Danish National Patient registry and the Cause of Death Register). | 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. |
1st trimester | 8590 / 471855 | Infants with chromosomal abnormalities (ICD-10 codes Q90– Q99) were excluded from all analyses. | |
| Exposure was determined using the Prescription register that contains individual-level prescription data from all Danish outpatient pharmacies. | ||||||||
|
Broe (Controls unexposed, sick) 2025 |
Denmark 2004 - 2017 population based cohort retrospective |
Danish national health registries (the Danish Medical Birth registry, the Danish Civil Registration Registry, the Danish National Prescription Registry, the Danish National Patient registry and the Cause of Death Register). | 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. |
1st trimester | 8590 / 14817 | Infants with chromosomal abnormalities (ICD-10 codes Q90– Q99) were excluded from all analyses. | |
| Exposure was determined using the Prescription register that contains individual-level prescription data from all Danish outpatient pharmacies. | ||||||||
|
Czeizel 2005 |
Hungary 1980 - 1996 retrospective cohort |
The 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. |
during pregnancy (anytime or not specified) | 173 / 37978 | In general, daily 300–1000 mg of paracetamol was used for between 3 and 8 days with a mean of 4 days. | |
| Exposure data collected from 3 sources: a post-paid structured questionnaire sent to the parents requesting drugs taken during pregnancy, according to gestational months; maternal prenatal care logbook (in which obstetricians must record all prescribed drugs); nurses visited non-responding families. | ||||||||
|
Dathe 2019 |
Germany 2008 - 2017 prospective cohort |
The Embryotox institute in Berlin, a well-established publicly funded institution that offers risk assessment on drug use in pregnancy to health care professionals (HCPs) and their pregnant patients. | 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. |
3rd 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). | |
| Relevant data on drug exposure (duration of treatment, dosage, and anatomical therapeutic chemical [ATC] codes), including co-medication as a potential confounding factor) are recorded in addition to the counselling process, then 8 weeks after the expected date of delivery. | ||||||||
|
De Castro 2022 |
Brazil 2012 - 2014 prospective cohort |
The Center for Research in Maternal and Child Health (NISAMI) cohort, state of Bahia, Brazil. | 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. |
during pregnancy (anytime or not specified) | 106 / 654 | ||
| Data were collected by trained interviewers during prenatal visits. The pregnant women were interviewed using a standardized questionnaire with 116 questions divided into 7 parts, including medication information (before and during pregnancy). | ||||||||
|
Fisher 2016 |
United Kingdom 2001 - 2009 prospective cohort |
The Cambridge Baby Growth Study (CBGS), a prospective cohort study conducted at the Rosie Maternity Unit, Addenbrooke‘s Hospital, Cambridge. | 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. |
1st trimester, during pregnancy (anytime or not specified) | 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. | |
| A printed questionnaire was given to women at the time of recruitment with instructions that it should be completed in time for collection ‘after your baby is born’, notably asking: ‘Have you taken any medicine during this pregnancy?’. If yes, gestational period and frequency were completed. | ||||||||
|
Garcia-Marcos 2009 |
Spain Not specified. retrospective cohort |
Epidemiological survey performed in 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. |
during pregnancy (anytime or not specified) | 717 / 806 | Number of exposed and unexposed: calculated based on table 1. | |
| Questionnaires were given to the parents by their children’s teachers and returned within 1 week. The questionnaires included a specific question on paracetamol consumption during pregnancy (never, at least once during pregnancy or at least once per month during pregnancy). | ||||||||
|
Goksor 2011 |
Sweden 2003 prospective cohort |
A prospective, longitudinal cohort study of children born in the region of western Sweden (urban, rural and coastal areas around the largest city Gothenburg). | Prenatal paracetamol exposure. |
unexposed (general population or NOS)
No prenatal paracetamol exposure. |
during pregnancy (anytime or not specified) | 334 / 4017 | ||
| The parents answered questionnaires at 6 and 12 months and at 4.5 years of age. Information regarding pregnancy and maternal intake of medical drugs during pregnancy were obtained from the 6-month questionnaire. | ||||||||
|
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. | ||||||||
|
Jedrychowski 2011 |
Poland 2001 - 2004 prospective cohort |
Prenatal clinics in the Krakow inner city area, Poland. | Prenatal intake of paracetamol whenever in pregnancy irrespective of dose. |
unexposed (general population or NOS)
No prenatal intake of paracetamol in pregnancy. |
during pregnancy (anytime or not specified) | 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). | |
| Paracetamol use in pregnancy was collected by interviews during and probably after pregnancy ('The information about medication taken in each of the post natal periods was gathered as well'). | ||||||||
|
Jensen 2010 |
Denmark 1996 – 2002 prospective cohort |
The Danish National Birth Cohort (DNBC), a population-based cohort of children born to women who were pregnant during 1996–2002 and who intended to carry their pregnancy to term, linked with the Danish National Patient Registry. | 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. |
1st and 2nd trimester, 1st trimester, 2nd and/or 3rd trimester, 2nd trimester, 3rd trimester, throughout 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). | |
| Data on exposure were collected both prospectively (before cryptorchidism could be recognized), by using the enrollment questionnaire and the 2 telephone interviews during pregnancy, and retrospectively during the telephone interview that took place 6 months postpartum. | ||||||||
|
Källén 2003 |
Sweden 1995 - 2001 population based cohort retrospective |
The Swedish Medical Birth Registry, the Swedish Registry of Congenital Malformations and the Swedish Child Cardiology Registry. | 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. |
early pregnancy | 36626 / 577730 | No result presented for any cardiovascular defect with chromosome anomaly. | |
| At the first antenatal visit (usually week 10–12), a midwife interviewed the woman on the use of drugs during the pregnancy before the antenatal care visit. Throughout the subsequent antenatal care, additional prescriptions for drugs are recorded and also computerized. | ||||||||
|
Killion 2022 |
USA and Canada 2004 - 2018 prospective cohort |
The MotherToBaby cohort study, a prospective cohort study with the objective of evaluating a variety of adverse pregnancy and birth outcomes in women who are pregnant and exposed to diseases or therapeutic agents relative to those who were unexposed. | 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. |
during pregnancy (anytime or not specified), early 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). | |
| Women completed up to four telephone surveys assessing exposures. An outcome interview updated late gestation information. All medications, including non-prescription medications, were self-reported at each phone interview, including start and stop dates, frequency, dosage and reason for use. | ||||||||
|
Kristensen 2011 |
Denmark Not specified prospective cohort |
Prospective birth cohort study conducted at the University Hospital of Copenhagen (Rigshospitalet and Hvidovre Hospital) in Denmark (only the computer assisted telephone interviews as part of the Danish National Birth Cohort were used). | 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). |
1st trimester, 2nd trimester, during pregnancy (anytime or not specified) | 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. | |
| Pregnant women in the third trimester were questioned concerning disease and medicine use during the pregnancy (self-administered written questionnaire, or computer assisted telephone interview). | ||||||||
|
Li 2003 |
USA 1996 - 1998 retrospective cohort (claims database) |
The Kaiser Permanente Medical Care Program—an integrated healthcare delivery system, including hospitals and outpatient clinics, that contracts exclusively with a single group of physicians —in northern California. | 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. |
during pregnancy (anytime or not specified) | 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. | |
| Information on use of non-steroidal anti-inflammatory drugs, aspirin, and paracetamol during pregnancy was obtained in an interview conducted soon after each woman’s pregnancy was confirmed (names of any drugs; conditions that they were to treat; timing, duration and frequency of their use). | ||||||||
|
Li (Controls exposed to NSAIDS) 2018 |
USA 2005 - 2012 retrospective cohort (claims database) |
The Kaiser Permanente Northern California (KPNC), USA. | 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. |
during pregnancy (anytime or not specified) | 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. | |
| Participants were interviewed in person by experienced interviewers. The interview collected detailed information on exposure to NSAIDs and acetaminophen during pregnancy. In addition, medications obtained from KPNC’s pharmacy database were verified with the participant. | ||||||||
|
Li (Controls unexposed, NOS) 2018 |
USA 2005 - 2012 retrospective cohort (claims database) |
The Kaiser Permanente Northern California (KPNC), USA. | 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. |
during pregnancy (anytime or not specified) | 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. | |
| Participants were interviewed in person by experienced interviewers. The interview collected detailed information on exposure to NSAIDs and acetaminophen during pregnancy. In addition, medications obtained from KPNC’s pharmacy database were verified with the participant. | ||||||||
|
Liew 2021 |
USA Jan 2003 - Dec 2003 retrospective cohort |
The Environment and Pregnancy Outcomes Study (EPOS) at the University of California, Los Angeles (UCLA), USA. | 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. |
1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) | 393 / 808 | Use of results of Table S1 (Model C of adjustment). | |
| Mothers were interviewed by phone or replied to a mailed survey in English or Spanish three to six months post-partum. Mothers provided detailed information on pregnancy exposures (medication, trimester and frequency) including over-the-counter medication use. | ||||||||
|
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. | ||||||||
|
Liew c 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 paracetamol during pregnancy. |
unexposed (general population or NOS)
Children born to mothers who never used paracetamol during pregnancy. |
1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) | 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. | |
| 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_Boys 2019 |
Denmark 1996 - 2002 prospective cohort |
The Danish National Birth Cohort (DNBC), a study by conducted about 50% of all general practitioners in Denmark. | 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). |
1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified), throughout pregnancy | 8582 / 7037 | ||
| Mothers completed the enrollment form and the three telephone interviews (approximately at gestational weeks 12 and 30 and 6 months after birth), during which information on acetaminophen intake during pregnancy was collected. | ||||||||
|
Liew_Girls 2019 |
Denmark 1996 - 2002 prospective cohort |
The Danish National Birth Cohort (DNBC), a study by conducted about 50% of all general practitioners in Denmark. | 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). |
1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified), throughout pregnancy | 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. | |
| Mothers completed the enrollment form and the three telephone interviews (approximately at gestational weeks 12 and 30 and 6 months after birth), during which information on acetaminophen intake during pregnancy was collected. | ||||||||
|
Magnus (Controls exposed to ibuprofen) 2016 |
Norway 1999 - 2008 prospective cohort |
The Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health, linked to the Medical Birth Registry of Norway and the Norwegian Prescription Database. | Prenatal exposure to paracetamol (without ibuprofen). |
exposed to other treatment, sick
Prenatal exposure to ibuprofen (without paracetamol). |
during pregnancy (anytime or not specified) | 22675 / 766 | ||
| Participating mothers reported the use of medications for different indications during pregnancy through questionnaires completed at 18 gestational weeks, 30 gestational weeks and when the child was 6 months old. | ||||||||
|
Magnus (Controls unexposed, NOS) 2016 |
Norway 1999 - 2008 prospective cohort |
The Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health, linked to the Medical Birth Registry of Norway and the Norwegian Prescription Database. | Prenatal exposure to paracetamol (and no exposure during infancy). |
unexposed (general population or NOS)
No prenatal or infant exposure to paracetamol. |
during pregnancy (anytime or not specified) | 14837 / 19912 | ||
| Participating mothers reported the use of medications for different indications during pregnancy through questionnaires completed at 18 gestational weeks, 30 gestational weeks and when the child was 6 months old. | ||||||||
|
Marild 2017 |
Norway 1999 - 2008 prospective cohort |
The nationwide Norwegian Mother and Child Cohort Study (MoBa), a prospective population-based pregnancy cohort study. | Any use of paracetamol during pregnancy, irrespective of the indication for use. |
unexposed (general population or NOS)
No use of paracetamol during pregnancy. |
during pregnancy (anytime or not specified) | 39117 / 45157 | ||
| Data on exposures were collected from questionnaires administered at weeks 18 and 30 of pregnancy (covering the period of the first 17 weeks of pregnancy and weeks 18 to 30 of pregnancy, respectively) and when the child is 6 months old (exposures after pregnancy week 30 and up until delivery). | ||||||||
|
Okubo (Controls unexposed, general population) 2025 |
Japan 2005 - 2022 retrospective cohort (claims database) |
The Japan Medical Data Center (JMDC), a nationwide administrative database developed to build a birth cohort of children born between April 2005 and March 2022. | Ever-use of acetaminophen during pregnancy. |
unexposed (general population or NOS)
No use of acetaminophen during pregnancy. |
during pregnancy (anytime or not specified) | 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. | |
| Acetaminophen use during pregnancy was identified from all prescription dispensation records using the Anatomical Therapeutic Chemical (ATC) codes. The exposure metric was the ever-use of acetaminophen during pregnancy. | ||||||||
|
Okubo (Controls unexposed, sibling) 2025 |
Japan 2005 - 2022 retrospective cohort (claims database) |
The Japan Medical Data Center (JMDC), a nationwide administrative database developed to build a birth cohort of children born between April 2005 and March 2022. | 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. |
during pregnancy (anytime or not specified) | 11696 / 11897 | Identification of 23,593 children who had discordant pairs of maternal acetaminophen use. | |
| Acetaminophen use during pregnancy was identified from all prescription dispensation records using the Anatomical Therapeutic Chemical (ATC) codes. The exposure metric was the ever-use of acetaminophen during pregnancy. | ||||||||
|
Persky 2008 |
USA Not specified. retrospective cohort |
The Peer Education in Pregnancy Study, a randomized controlled trial examining the effect of community educators working with pregnant women at risk for having children with asthma, USA. | Acetaminophen use during pregnancy. |
unexposed (general population or NOS)
No acetaminophen use during pregnancy. |
1st trimester, 2nd and/or 3rd trimester, during pregnancy (anytime or not specified) | 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. | |
| Acetaminophen use was determined from 4 different questionnaires: (1) at enrollment (first trimester); (2) at the second visit (4-5 months of gestation); (3) at the third visit (7-8 months of gestation); and (4) at the first postpartum visit (visit 4). | ||||||||
|
Perzanowski 2010 |
USA 1998 - 2006 prospective cohort |
The Columbia Center for Children’s Environmental Health (CCCEH), New York, USA. | Mothers that reported acetaminophen use during pregnancy. |
unexposed (general population or NOS)
Mothers that did not report acetaminophen use during pregnancy. |
1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) | 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. | |
| Use of acetaminophen, ibuprofen and aspirin during pregnancy was ascertained in the third trimester. Mothers complete prenatal questionnaire items on analgesic use. | ||||||||
|
Petersen 2018 |
Denmark and Norway 1996 - 2008 prospective cohort |
The MOthers and BAbies in Norway and Denmark (MOBAND) cohort, comprising pooled data from the Danish National Birth Cohort (DNBC) and the Norwegian Mother and Child Cohort Study (MoBa). | 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). |
1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) | 91015 / 71345 | ||
| Exposure was collected in DNBC in the enrolment form and with computer-assisted telephone interviews at gw 16 and 31. In MoBa, these data were collected by self-administered questionnaires at gw 17 and 30. Later exposures were covered by data collections 6 months after delivery, in both sub-cohorts. | ||||||||
|
Pleau 2025 |
Canada 1998 - 2015 retrospective cohort (claims database) |
The Quebec Pregnancy Cohort, a prospective population-based pregnancy cohort that includes the data from all pregnancies and their children covered by Quebec prescription medication insurance. | 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). |
2nd and/or 3rd 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. | |
| Prescriptions from the Quebec prescription medication insurance. | ||||||||
|
Rebordosa 2010 |
Denmark 1996 - 2003 prospective cohort |
The Danish National Birth Cohort (DNBC) is a nationwide cohort study with long-term follow-up, linked to the National Hospital Discharge Registry (NHDR). | 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. |
1st trimester, 2nd trimester, 3rd trimester | 35992 / 27841 | Dose-response relationship provided only for Acetaminophen use during the third trimester of pregnancy (not provided for 1st trimester). | |
| Exposure information was collected several times during pregnancy in order to facilitate recall, with the help of computer-assisted telephone interviews with the women twice during pregnancy (around the 12th and 30th week) and when the children were 6 and 18 months and 7 years of age. | ||||||||
|
Rebordosa 2009 |
Denmark 1996 - 2003 prospective cohort |
The Danish National Birth Cohort (DNBC), a population-based cohort study of approximately 100000 newborns recruited between 1996 and 2003, linked to the National Hospital Registry (NHR) and to the Medical Birth Registry (MBR). | 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). |
1st trimester, during pregnancy (anytime or not specified) | 50702 / 47438 | Women who delivered live born children reported having used acetaminophen on average 9.4 weeks during pregnancy. | |
| Exposures were identified from responses in the enrolment questionnaire and from the first, second or third telephone interviews (at 12th and 30th gestational weeks and when the child was 6 months old). | ||||||||
|
Rebordosa a 2008 |
Denmark 1996 - 2003 prospective cohort |
The Danish National Birth Cohort (DNBC), a nationwide study of 100,000 pregnant women and their offspring, linked to the National Hospital Registry (NHR). | 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. |
1st trimester, during pregnancy (anytime or not specified) | 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). | |
| Data were mainly through 4 computer-assisted follow-up telephone interviews and a self-administered questionnaire at enrollment. Telephone interviewing took place at scheduled times and participants were asked to have prescriptions or medication packets available at the time of interviewing. | ||||||||
|
Rebordosa b 2008 |
Denmark 1996 - 2003 prospective cohort |
The Danish National Birth Cohort (DNBC), a population-based cohort study of approximately 100000 newborns recruited between 1996 and 2003. | 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). |
during pregnancy (anytime or not specified) | 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. | |
| Women were asked to complete a self-administered enrolment questionnaire and participate in four telephone interviews (two during pregnancy and two more when the child was 6 months and 18 months of age). Information about paracetamol, aspirin and ibuprofen use was obtained from the interviews. | ||||||||
|
Rifas-Shiman 2020 |
USA 1999 - 2002 prospective cohort |
The pre-birth cohort study Project Viva, recruiting in early pregnancy from 8 obstetric offices of Atrius Harvard Vanguard Medical Associates, a multispecialty group 15 practice in eastern Massachusetts. | Pregnant women reporting use of acetaminophen during pregnancy. |
unexposed (general population or NOS)
Pregnant women that did not report use of acetaminophen during pregnancy. |
during pregnancy (anytime or not specified) | 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. | |
| Intake of acetaminophen and ibuprofen were asked to pregnant women during interviews conducted during early (median 9.9 weeks of gestation) and mid-pregnancy (median 27.9 weeks of gestation), categorize as never, 1–9 times, or ≥10 times. | ||||||||
|
Rumack 1981 |
USA Not specified. prospective cohort |
The level 3 neonatal intensive care nurseries of Denver General and Colorado General Hospitals, USA. | 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. |
days before delivery | 20 / 71 | ||
| A complete drug history was obtained from the mother on day 2 post partum to determine whether any medication containing either aspirin or acetaminophen was ingested during the last week of pregnancy. | ||||||||
|
Shaheen (Controls unexposed, general pop) 2019 |
Sweden 2005 - 2010 population based cohort retrospective |
Swedish national health registers (Medical Birth Register, Migration Register, National Patient Register, Swedish Prescribed Drug Register, Multi-Generation Register and Register of the Total Population dates of death). | 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. |
during pregnancy (anytime or not specified) | 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. | |
| Information on prescribed analgesics dispensed during pregnancy was collected from the Swedish Prescribed Drug Register (SPDR) that contains information on prescription and dispense dates, number of packages, and dosage of all prescribed medications dispensed in Swedish pharmacies. | ||||||||
|
Shaheen (Controls unexposed, sibling) 2019 |
Sweden 2005 - 2010 population based cohort retrospective |
Swedish national health registers (Medical Birth Register, Migration Register, National Patient Register, Swedish Prescribed Drug Register, Multi-Generation Register and Register of the Total Population dates of death). | 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. |
during pregnancy (anytime or not specified) | -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. | |
| Information on prescribed analgesics dispensed during pregnancy was collected from the Swedish Prescribed Drug Register (SPDR) that contains information on prescription and dispense dates, number of packages, and dosage of all prescribed medications dispensed in Swedish pharmacies. | ||||||||
|
Smith-Webb 2023 |
United States and Canada 1996 - 2002 retrospective cohort |
A case-control study of prenatal exposures and craniofacial malformation in infants, ascertained from 26 craniofacial centers across the United States and Canada. | 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. |
during pregnancy (anytime or not specified) | 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. | |
| Information on acetaminophen use during pregnancy was collected via standardized telephone interview after delivery and prior to conduct of any neurodevelopmental assessments of the child. Maternal exposures collected on average 12 months after delivery (IQR: 3–18 months). | ||||||||
|
Snijder 2012 |
The Netherlands 2002 - 2006 prospective cohort |
The Generation R Study, a large population-based prospective birth cohort study from early pregnancy onwards in the Netherlands. | 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. |
1st trimester, 2nd trimester, 3rd trimester, periconceptional | -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. | |
| The three self-administered questionnaires assessed medication use during pregnancy and were sent out by post at gestational weeks 12, 20 and 30 with an average lag period to response of about 2 weeks. | ||||||||
|
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. | ||||||||
|
Tapia 2018 |
Norway 1999 - 2008 prospective cohort |
The Norwegian Mother and Child Cohort Study (MoBa), the Norwegian Childhood Diabetes Registry and the Norwegian Patient Register (NPR). | Acetaminophen exposure in pregnancy. |
unexposed (general population or NOS)
No acetaminophen exposure in pregnancy. |
during pregnancy (anytime or not specified) | -9 / -9 | Number of exposures and non exposures not provided by authors. | |
| Maternal pregnancy exposures were assessed by questionnaires that are available at [www.fhi.no/moba], administered at pregnancy weeks 17 and 30, and at child’s age 6 months (covering pregnancy weeks 0–17, 18–30 and 30 until delivery, respectively). | ||||||||
|
Thulstrup 1999 |
Denmark 1991 - 1996 retrospective cohort (claims database) |
Record linkage between the North Jutland Prescription Database of the Denmark, the Danish Birth Registry and the Danish Hospital Registry. | 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. |
1st trimester, 2nd and/or 3rd trimester, during pregnancy (anytime or not specified) | 123 / 13329 | ||
| The North Jutland Prescription Database of the Denmark was used to examined the exposure. The county is served by 33 pharmacies equipped with a computerized accounting system from which data are sent to the health insurance administration of the Danish National Health Service. | ||||||||
|
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. | ||||||||
|
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). | ||||||||
|
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 maximalist duration (i.e 3 trimesters). | |
| 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 maximalist duration (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). | ||||||||
|
Walker 2024 |
New Zealand 2009 - 2010 prospective cohort |
The Growing Up in New Zealand (GUiNZ) longitudinal child development study. | 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). |
during pregnancy (anytime or not specified) | 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). | |
| Prenatally, mothers provided potential teratogens (e.g., drug use). Mothers were asked whether or not (yes or no) they have taken certain types of medications in the first three months and after the first three months of pregnancy. | ||||||||
|
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. | ||||||||
|
Xu 2024 |
China 2018 - 2023 retrospective cohort |
The Beijing Obstetrics and Gynecology Hospital affiliated with Capital Medical University, China. | 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. |
1st and 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) | 501 / 501 | ||
| Data were extracted from the electronic medical record (EMR) system, where the patient has a unique code to support the inquiry and tracking of patient medical records and medication information. | ||||||||
|
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 maximalist duration (i.e >= 29 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). | ||||||||
|
Zafeiri 2022 |
Scotland 1985 - 2015 retrospective cohort |
Data collected in the Aberdeen Maternity and Neonatal Databank (AMND) in Aberdeen, Scotland, UK. | Consumption of Paracetamol only (among analgesic) during pregnancy. |
unexposed (general population or NOS)
No analgesic consumption (paracetamol, ibuprofen, naproxen, diclofenac or aspirin) during pregnancy. |
during pregnancy (anytime or not specified) | 24099 / 107143 | ||
| Data were collected from medical notes of women retrospectively after delivery. Women were specifically asked about their use of over-the-counter (non-prescription) analgesics at their first antenatal clinic. Constant data cleaning and validation against case notes reported quarterly. | ||||||||
| 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). | |||||||||
|
Cifuentes 2025 |
Europe (13 countries) 1995 - 2019 case control |
A case-malformed-control study using the EUROmediCAT database, including data from data from 19 registries from EUROCAT the European network for surveillance of congenital anomalies and from EFEMERIS. | 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. | Information on maternal medication exposure was primarily obtained from maternity records. Additional data sources for some registries included: infant medical records, general practitioner records, pregnancy passports, and maternal interviews conducted before or after birth. EFEMERIS: dispensing. | 1st trimester | 4185 / 232718 | Use of nongenetic controls (cases of congenital anomalies other than congenital ocular anomalies excluding genetic syndromes). | |
| Cases and controls were obtained in registries from EUROCAT, the European network for surveillance of congenital anomalies. | |||||||||
|
Couto 2015 |
Brazil 1999 - 2007 case control |
The ‘Multi-Institutional Study of Infant Leukemia: Contribution of Immunomolecular Markers in Distinguishing Different Etiopathogenic Factors’, Brazil. | 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. | Information the use of drugs and the time window of exposure to analgesics was obtained through a specifically designed and standardized survey. Face-to- face interviews were performed with the mothers of cases and controls to obtain information. | 1st trimester, 2nd trimester, 3 months (or more) before pregnancy or during pregnancy, 3rd trimester | 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). | |
| The patients were recruited from oncologic hospitals in the following cities in 11 states: Belo Horizonte, Brasília, Campinas, Campo Grande, Curitiba, Florianópolis, Goiânia, João Pessoa, Recife, Rio de Janeiro, Salvador, Santa Maria, and São Paulo. | |||||||||
|
Feldkamp 2010 |
USA 1997 - 2004 case control |
The National Birth Defects Prevention Study (NBDPS), an ongoing, multicenter, population-based, case-control study of major birth defects ascertained from 10 centers in the United States. | 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. | Trained interviewers administered a computer-assisted telephone interview to mothers of children in the case and control groups (acetaminophen consumption was specifically queried). Every woman was queried about medication use from 3 months before conception through the entire pregnancy. | 1st trimester | 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. | |
| Major birth defects ascertained from 10 centers in the United States collected by birth-defects surveillance programs at each center. | |||||||||
|
Given 2017 |
14: Belgium, Croatia, Denmark, FR, Germany, Ireland, Italy, Netherlands, Norway, Ukraine, UK... 1995 - 2012 case control |
A case-malformed control study based on EUROmediCAT, a population based reproductive pharmacovigilance system, based on the European Surveillance of Congenital Anomalies (EUROCAT) network. | 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. | First trimester maternal medication exposures were mostly obtained by registries from prospectively recorded maternity records. Additional data sources included the medical records of the infant, general practitioner records, maternity passports, and maternal interviews before or after birth. | 1st trimester | 1587 / 154877 | Medications taken in the second or third trimester or where the timing was unknown were excluded. | |
| EUROCAT registries that record all cases of major congenital anomalies among live births, foetal deaths ≥20 weeks’ gestation and termination of pregnancy for foetal anomaly (TOPFA), in their populations using International Classification of Diseases (ICD)-9/10. | |||||||||
|
Goodman 2019 |
USA 2010 - 2012 case control |
The University of Oklahoma Health Sciences Center (OUHSC) obstetric clinic system, USA. | 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. | Patients reported any use of over the counter or prescribed medications in the month prior to or during pregnancy, data obtained by interview at enrollment (mid-pregnancy ultrasound). | during pregnancy (anytime or not specified) | 30 / 76 | Women with multiple pregnancies or a fetus known to have lethal anomalies, and/or chromosome abnormalities were excluded. | |
| Diagnostic ultrasounds in the obstetric clinic system of the University of Oklahoma Health Sciences Center (OUHSC). | |||||||||
|
Kerr 2019 |
USA and Canada 1993 - 2015 case control |
Slone Epidemiology Center Birth Defects Study (BDS) | Infants with microcephaly alone (“isolated”) and microcephaly that included other major birth defects (“non-isolated”), | Nonmalformed live-born infants. | Within 6 months of delivery, trained Birth Defects Study (BDS) nurse- interviewers contacted mothers to complete a roughly 1-hr computer-assisted telephone interview, including medications during pregnancy. | 1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) | 166 / 12059 | Authors analyzed separately 'isolated' microcephaly and 'non-isolated' microcephaly. Only isolated microcephaly are indexed in MetaPreg. | |
| Cases and controls were ascertained at participating hospitals or birth defect registries in the same areas. | |||||||||
|
Koniman 2007 |
Singapore 2005 - 2006 case control |
The paediatric outpatient clinics and the 'I CAN' (The Children’s Asthma and Allergy Network) programme at the National University Hospital (NUH), Singapore. | 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). | Paracetamol intakes of the mother during pregnancy were assessed using questionnaire interviewer-administered to the mother. If the response was positive for paracetamol intake, details regarding period of intake, the frequency, duration of intake, daily dose and indications were asked. | during pregnancy (anytime or not specified) | 38 / 42 | ||
| Cases were recruited from the paediatric outpatient clinics and the Children’s Asthma and Allergy Network programme at the National University Hospital, Singapore. The health status of the sibling was determined by questioning to the parent. All patients were subjected to skin prick testing. | |||||||||
|
Li 2021 |
Taiwan 1998 - 2008 nested case control |
The Taiwan Longitudinal Health Insurance Database, a compulsory and universal health insurance program offering comprehensive medical care coverage to all residents of Taiwan. | 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. | The Taiwan's 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) | 2529 / 5058 | ||
| The Taiwan's Longitudinal Health Insurance Database that contains comprehensive data on insured individuals, including clinical visit dates, disease diagnoses. The codes of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) are used for disease diagnosis. | |||||||||
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Lind 2013 |
USA 1997 - 2007 case control |
The National Birth Defects Prevention Study (NBDPS), a multi-site, population-based, case-control study. | 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. | The National Birth Defects Prevention Study uses computer-assisted telephone interviews to collect information from women 6 weeks to 24 months after their estimated date of delivery. | 1st trimester | 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. | |
| Cases are identified through population-based birth defects surveillance from each states. A clinical geneticist classifies eligible cases of hypospadias as isolated. | |||||||||
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Malaeb 2021 |
Lebanon Jan - Sep 2017 case control |
Lebanese students from public and private schools, from schools randomly selected based on the list of the Lebanese Ministry of Higher Education. | 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). | The questionnaire used was self-administered, anonymous, in Arabic and assessing behaviors during pregnancy like OTC medication use (questionnaires were distributed when students were grades 1 and 9). | during pregnancy (anytime or not specified) | 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. | |
| A standardized questionnaire fill out by parents to document asthma status and evaluate respiratory symptoms using validated International Study of Asthma and Allergies in Childhood (ISAAC) items. Students were asked to take it home, fill it out by their parents, and return it to school. | |||||||||
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Nelson 1971 |
United Kingdom 2 years period (NOS) case control |
Three hospital maternity units, University of Edinburgh, Scotland, UK. | 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. | All mothers were interviewed before discharge from maternity units to complete a questionnaire on drugs consumed during pregnancy. Finally, an attempt was made to recover the prescriptions issued to the mothers as proof that they had been taken for dispensing and as a record of the drugs supplied. | 1st trimester, during pregnancy (anytime or not specified) | 478 / 911 | ||
| In the hospitals the antenatal and other outpatient records and inpatient records were studied. For general practitioners of mothers included in the survey: 53% were seen personally and 37% provided information by telephone and/or questionnaire (10 % non responders). | |||||||||
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Ognjanovic 2011 |
Canada, USA 1996 - 2006 case control |
The Children’s Oncology Group (COG) institutions in the United States or Canada. | 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. | Information was collected through computer-assisted telephone interviews with the biological mother. Analgesic questions included maternal use of aspirin, acetaminophen and non-aspirin NSAIDs, including the frequency of use during these two time periods. | during pregnancy (anytime or not specified), early pregnancy | 434 / 323 | ||
| Detailed reports on leukaemia cell cytogenetics and molecular abnormalities were obtained for cases and included leukaemia subtype (lymphoblastic or myeloid) and MLL gene translocation status. | |||||||||
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Pastore 1999 |
USA Year 1984 case control |
A case-control study of stillbirths in 10 California agricultural, counties, primarily in the San Joaquin Valley, California, USA. | 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. | Month-by-month exposure information was asked for most, but not all, variables of interest. The time between delivery and completion of the questionnaire varied between 2 and 4 years. | 1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) | 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. | |
| Data sources included birth certificates, fetal death certificates and a postal questionnaire. | |||||||||
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Pérez-Molina 2002 |
Mexico 1989 - 1997 case control |
The Hospital Civil de Guadalajara 'Dr. Juan I. Menchaca', Guadalajara, Mexico. | 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. | Exposure data were obtained through a direct interview with the mothers of the study subjects, using structured questionnaires with closed-ended questions designed to document prior exposure to the studied variables. | 1st trimester | 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. | |
| Records corresponding to the cases and controls were extracted from the general congenital malformation database, and the original questionnaires were reviewed in detail to verify the clinical descriptions of each neural tube defect. | |||||||||
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Poletta 2012 |
South America 1967 - 2008 case control |
The Latin American Collaborative Study of Congenital Anomalies (ECLAMC). | 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. | Data regarding medication use and illnesses during pregnancy were obtained by qualified physicians using standard interviews of the mothers before their discharge from the hospital at which they had given birth. | 1st trimester | 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). | |
| Live-birth cases were those that were registered by the Latin American Collaborative Study of Congenital Anomalies (ECLAMC) network (no other details). | |||||||||
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Puho 2007 |
Hungary 1980 - 1996 case control |
Hungarian Case-Control Surveillance of Congenital Abnormalities | Cases with isolated cleft lip with or without cleft palate (CL/P) and posterior cleft palate (PCP). | Newborn infants without congenital abnormalities | Mothers were asked to send their prenatal maternity logbook and other medical records and they were mailed a questionnaire. Regional nurses were asked to visit and question the non-respondent. | 1st trimester | 1975 / 38151 | ||
| Notification by physicians to the Hungarian Congenital Abnormality Registry. Pathologists sent a copy of each autopsy report to the registry for stillborn fetuses or infant deaths and defect diagnosed in prenatal diagnostic centers with or without termination of pregnancy were included. | |||||||||
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Robledo-Aceves 2015 |
Mexico 2009 - 2013 case control |
The Hospital Civil de Guadalajara 'Dr. Juan I. Menchaca', Guadalajara, Mexico. | 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. | The record used by the Centro de Registro y Investigación sobre Anomalías Congénitas (CRIAC) contained standardized questions concerning notably maternal exposures during the periconceptional period and prescription drugs. No other details. | 1st trimester | 90 / 180 | ||
| The delivery and birth data were obtained directly from the hospital records. | |||||||||
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Ross 2003 |
USA and Canada 1983 - 1988 case control |
The registration files of the former Children’s Cancer Group (CCG) and general population. | 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. | Exposure information was collected from mothers using a structured telephone questionnaire. All prescription drugs recorded in the medical record were abstracted, including data for the trimester of pregnancy the drug was prescribed based upon gestational ages recorded in medical records. | during pregnancy (anytime or not specified) | 243 / 393 | ||
| Signed medical record release forms were obtained and complete copies of medical records were requested. Data were abstracted from medical records by two registered nurses using a structured protocol. | |||||||||
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Torfs 1996 |
USA 1989 - 1990 case control |
The California Birth Defects Monitoring Program (CBDMP), an active registry of birth defects in urban and rural counties of California. | 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. | Specially trained interviewers administered a 2-hour structured questionnaire to case and control mothers in their homes. Mothers were asked about the medications, either prescribed or bought over the counter, that were used to treat their illnesses. | 1st trimester | 110 / 220 | ||
| All birthing and tertiary referral hospitals in the counties surveyed, as well as genetic laboratories, are visited periodically, and all obstetric, nursery, and pathology logs are reviewed to identify infants with possible birth defects. Review of hospital charts of all cases. | |||||||||
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Werler 2002 |
USA and Canada 1995 - 1999 case control |
Case-control study conducted in 15 cities across the United States and Canada, from the Slone Epidemiology Unit. | 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). | A nurse-interviewer administered the standardized questionnaire by telephone within 6 months after delivery. Information was collected notably on medication histories The interviewer was not blinded to case/control status. | 1st trimester | 332 / 798 | No overlapping between Werler 1992 (1976-1990) and Werler 2002 (1995 - 1999). Single use preferred at acetaminophen in combination. | |
| Study subjects were ascertained from 29 pediatric tertiary care hospitals within 5 months of birth (no other details). | |||||||||
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Werler 2014 |
USA 2007 - 2011 case control |
The Slone Epidemiology Center Birth defect study - A population-based case-control study of medical record–confirmed clubfoot. | 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. | Mothers were interviewed by telephone within 12 months after delivery about medication use, including indication, product, timing, and frequency. | 1st trimester | 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.' | |
| Study subjects were ascertained from birth defect registries in Massachusetts, New York, and North Carolina. Mothers were then interviewed and an orthopedist reviewed the children’s pediatric and orthopedic records (77% agreed). Controls identified from birth certificates or hospital records. | |||||||||
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Werler 2003 |
USA 1976 - 1998 case control |
The ongoing Boston University Slone Epidemiology Center Birth Defects Study, USA. | 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). | Mothers of study subjects are interviewed by a study nurse within 6 months of delivery about events and exposures during pregnancy. | 1st trimester | 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). | |
| Liveborn and stillborn infants with major malformations are identified at birth and tertiary hospitals in the greater metropolitan areas of Boston, Philadelphia, and Toronto. | |||||||||
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Werler 1992 |
USA 1976 - 1990 case control |
The Boston University Slone Epidemiology Unit Birth Defects Study, an on-going case-control surveillance program, USA. | Infants with gastroschisis. | Infants with malformations other than gastroschisis, other defects thought to have a possible vascular etiology or chromosomal anomalies. | Mothers of infants with any of a range of birth defects were interviewed within 6 months after delivery about events and exposures during pregnancy, including medication use (from the 6 months prior to pregnancy through delivery). The median interval between delivery and interview was 4 months. | 1st trimester | 76 / 2142 | No overlapping between Werler 1992 (1976-1990) and Werler 2002 (1995 - 1999). | |
| Cases and controls were drawn from the Boston University Slone Epidemiology Unit Birth Defects Study, an on-going case-control surveillance program. Medical records were available to review for 46 potential cases and the diagnosis of gastroschisis was confirmed for 45 of them. | |||||||||
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Winship 1984 |
United Kingdom Jan 1981 - Dec 1981 case control |
The Committee on Safety of Medicines (CSM) by the Office of Population Censuses and Surveys (OPCS), United Kingdom. | 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. | Information of the drugs prescribed was obtained from the family doctors' records only and is therefore, not necessarily a complete record of drugs taken (it excluded hospital prescriptions and over the counter medicines). | 1st trimester | 764 / 764 | ||
| Information on each study and control child and their mothers was obtained from the records of the family doctors, who were interviewed by part time medical officers of the Committee on Safety of Medicines (CSM). Data were notably collected on outcome of pregnancy and congenital abnormality. | |||||||||
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Zarante 2009 |
Colombia 2001- 2006 case control |
The Institute of Human Genetics of the Pontificia Universidad Javeriana, an active member of the Latin-American Collaborative Study of Congenital Malformations (ECLAMC) which is an international registry of congenital malformations . | 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. | Information collected in 10 Colombian hospitals (NOS). | during pregnancy (anytime or not specified) | 374 / 728 | ||
| Information collected in 10 Colombian hospitals (NOS). | |||||||||
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Zierler 1985 |
United States 1980 - 1983 case control |
Massachusetts births, and in particular the New England Regional Infant Cardiac Program (NERICP), Massachusetts, USA. | 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. | Exposure data was obtained from detailed telephone questionnaires administered by one interviewer with questions designed to prompt recall of drug use and reasons for such use. The second source of exposure information was obstetric records of mothers of controls and affected children. | 1st trimester | 298 / 738 | The authors provided a 90% confidence interval, without adjustment => here a 95% confidence interval was calculated to be homogeneous with other studies. | |
| Cases mainly identifier from the New England Infant Cardiac Registry according to diagnoses of the cardiac defect recorded in medical records. Controls were randomly selected from available birth certificates filed with the Massachusetts Division of Health Statistics. | |||||||||
Risk of bias: : NA; : low; : moderate; : serious; : critical; : unclear;
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