| 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 |
|---|---|---|---|---|---|---|---|---|
|
Andrews 2003 |
USA 1996 - 2000 randomized controlled trial |
A randomized double-masked trial conducted by the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (NICHD MFMU) Network. | Oral metronidazole 250 mg three times daily plus erythromycin 250 mg four times daily for 10 days, between 21 weeks 0 days and 25 weeks 6 days of gestation. |
unexposed, sick
Oral placebo capsules for 10 days, between 21 weeks 0 days and 25 weeks 6 days of gestation. |
2nd trimester | 353 / 362 | EXCLUDED: Study related to an acute pathology of the pregnancy, where the outcomes were studied to establish the efficacy of treatment rather than safety, thus not reported in metaPreg. | |
| Subjects were instructed to take medications or placebo. Medication compliance was estimated at this visit by examining the pill containers for remaining capsules. | ||||||||
|
Diav-Citrin 2001 |
Israel 1989 - 1998 prospective cohort |
The Israeli Teratogen Information Service (TIS) | Women exposed to metronidazole in pregnancy (including a subgroup of patients exposed to metronidazole during gestational weeks 5–12). |
unexposed (general population or NOS)
Pregnant women who had been counseled in regard to exposures not known to be teratogenic. |
1st trimester, during pregnancy (anytime or not specified) | 228 / 629 | Most patients in the cohort (90.4%) used the medication orally; 6.0% used it by suppositories; 3.6% by the intravenous route. => Considered as Oral route. | |
| Details of exposure were collected during pregnancy, using a structured questionnaire. | ||||||||
|
Heinonen (Controls exposed to penicillins) 1977 |
USA 1959 - 1965 prospective cohort |
The Collaborative Perinatal Project: 14 university-affiliated hospitals | Pregnant women exposed to systemic Metronidazole during lunar months 1-4. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Pregnant women exposed to systemic Penicillin derivates during lunar months 1-4. (This is a subgroup of exposure among the whole exposed group considered in the study). |
1st trimester | 31 / 3546 | ||
| Extensive information on drugs taken during pregnancy was collected before the birth of the child. Data on drug were recorded at each antenatal visit and confirmed, with few exceptions, by the attending physician or by the hospital or clinic record. | ||||||||
|
Heinonen (Controls unexposed, NOS) 1977 |
USA 1959 - 1965 prospective cohort |
The Collaborative Perinatal Project: 14 university-affiliated hospitals | Pregnant women exposed to systemic Metronidazole during lunar months 1-4. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
Pregnant women not exposed to systemic Metronidazole during lunar months 1-4. |
1st trimester | 31 / 50251 | ||
| Extensive information on drugs taken during pregnancy was collected before the birth of the child. Data on drug were recorded at each antenatal visit and confirmed, with few exceptions, by the attending physician or by the hospital or clinic record. | ||||||||
|
Jeffcoat 2003 |
USA Not specified prospective cohort |
The pilot dental trial from a large prospective blinded, controlled, randomized clinical trial conducted in the periodontal clinic at the University of Alabama at Birmingham (UAB). | Pregnant women with scaling and root planing (SRP) plus metronidazole 250 mg three times a day for 1 week. |
unexposed, sick
Pregnant women with scaling and root planing (SRP) plus placebo capsule three times a day for 1 week. |
2nd trimester | 120 / 123 | ||
| Patients were randomly assigned to one of three treatment groups. An University of Alabama at Birmingham (UAB) research pharmacist, who provided a double packet with coding information for each patient, generated the randomization code. | ||||||||
|
Kamal 2018 |
Egypt 2014 - 2015 prospective cohort |
The antenatal care clinic of Minia Maternity and Pediatric University Hospital, Minia, Egypt. | Pregnant women with trichomoniasis. All positive cases were treated with metronidazole administered orally 500mg twice a day for 7 days. |
unexposed, disease free
Pregnant women without trichomoniasis. |
2nd and/or 3rd trimester | 35 / 265 | Study on the efficacy of azole in an obstetrical indication, including the intrauterine deaths and/or late pregnancy and/or neonatal outcomes that are studied as efficacy criteria rather than safety one. => Not reported here. | |
| All positive cases were treated with metronidazole administered orally 500mg twice a day for 7 days. | ||||||||
|
Koss 2012 |
USA 2000 - 2002 retrospective cohort |
A cohort study of treatment for bacterial vaginosis (BV) in pregnancy to reduce adverse birth outcomes. | Pregnant women treated with metronidazole, defined as the first documented occurrence of treatment during pregnancy with oral or intravenous metronidazole. Intravaginal doses were excluded. |
unexposed, disease free
Pregnant women not treated with metronidazole. |
1st trimester, 2nd and/or 3rd trimester, during pregnancy (anytime or not specified) | 922 / 1974 | 'Intravaginal doses were excluded, as the peak metronidazole serum concentration after a 5-g intravaginal dose of 0.75% metronidazole gel (37.5 mg metronidazole) is less than 2% of that after a 500-mg oral dose.' | |
| Prenatal care and hospital records of mothers were reviewed to determine whether metronidazole treatment occurred. Chart reviewers were blind to the purpose of the study. | ||||||||
|
Mann 2009 |
USA 1996 - 2002 retrospective cohort (claims database) |
South Carolina Medicaid billing records and birth certificate data. | Women with trichomoniasis (diagnosed at least 30 days prior to delivery) were considered treated if they filled a prescription for oral metronidazole within 14 days of the first diagnosis of trichomoniasis. |
unexposed (general population or NOS)
All other women were considered untreated. |
during pregnancy (anytime or not specified) | -9 / -9 | ||
| Treatment status was determined by using Medicaid outpatient pharmacy billing records, which provided drug names and dates dispensed. | ||||||||
|
Morgan 1978 |
England 1971 - 1976 retrospective cohort |
Hammersmith Hospital, England | Pregnant women with trichomoniasis who received 7 or 10 day courses of oral metronidazole (200 mg three times a day). |
unexposed, sick
Pregnant women with trichomoniasis who were untreated. |
during pregnancy (anytime or not specified) | 597 / 283 | Study on the efficacy of azole in an obstetrical indication, including the intrauterine deaths and/or late pregnancy and/or neonatal outcomes that are studied as efficacy criteria rather than safety one. => Not reported here. | |
| Not specified. | ||||||||
|
Muanda a (Controls exposed to penicillins) 2017 |
Canada 1998 – 2008 retrospective cohort (claims database) |
The Quebec Pregnancy Cohort, an ongoing population-based cohort with prospective data collection. | Having filled at least one prescription for Metronidazole within the first trimester of pregnancy or before pregnancy but with a duration that overlapped the first day of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study). |
exposed to other treatment, sick
Having filled at least one prescription for Penicillins within the first trimester of pregnancy or before pregnancy but with a duration that overlapped the first day of gestation. |
1st trimester | 412 / 9106 | Pregnancies with exposure to known teratogens during the first trimester, chromosomal aberrations and minor malformations were also excluded. | |
| The Quebec Public Prescription Drug Insurance database (drug name, start date, dosage and duration). Filled prescription of antibiotics within the QPC has been validated against maternal reports with high positive and negative predictive value (PPV 86.7% and NPV 92.3%). | ||||||||
|
Muanda a (Controls unexposed, NOS) 2017 |
Canada 1998 - 2008 retrospective cohort (claims database) |
The Quebec Pregnancy Cohort, an ongoing population-based cohort with prospective data collection. | Pregnancies having filled at least one prescription for Metronidazole within the first trimester of pregnancy or before pregnancy but with a duration that overlapped the first day of gestation. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
Pregnancies with no exposure to antibiotic during the time window of interest. |
1st trimester | 412 / 124469 | ||
| Exposure identified from the Quebec Public Prescription Drug Insurance database (drug name, start date, dosage and duration). Filled prescription of antibiotics within the QPC has been validated against maternal reports with high positive and negative predictive value (PPV 86.7% and NPV 92.3%). | ||||||||
|
Piper 1993 |
USA 1983 - 1988 retrospective cohort (claims database) |
Tennessee Medicaid files | A prescription for metronidazole between 30 days before and 120 days after the onset of the last normal menstrual period (LMP). |
unexposed (general population or NOS)
Comparable women enrolled in Medicaid who did not fill a prescription for metronidazole during the index period. |
1st trimester | 1307 / 1311 | Minor abnormalities and conditions that were recorded inconsistently in delivery facilities were not considered birth defects. | |
| Prescription drug use during pregnancy was ascertained from Medicaid pharmacy files, which included the date the prescription was dispensed and the days of supply. | ||||||||
|
Sorensen 1999 |
Denmark 1991 - 1996 retrospective cohort (claims database) |
A population-based cohort study in North Jutland County, Denmark. | Pregnant women redeeming prescriptions for metronidazole, classified according to two time windows. |
unexposed (general population or NOS)
Pregnant women not exposed to any kind of reimbursed medicine during pregnancy. |
1st trimester, during pregnancy (anytime or not specified) | 124 / 13327 | ||
| All prescription data have been stored in the Pharmaco-Epidemiological Prescription Database of North Jutland. | ||||||||
|
Thapa 1998 |
USA 1975 - 1992 retrospective cohort |
Tennessee Medicaid and a childhood cancer database for Tennessee. | Metronidazole use at any time during the pregnancy, defined as any filled prescription for metronidazole for at least 1 day’s supply between 30 days before the Last menstrual period (LMP) and the date of delivery. |
unexposed (general population or NOS)
No metronidazole use during the pregnancy. |
during pregnancy (anytime or not specified) | 79716 / 1092980 | Number of exposed and unexposed in person-years. | |
| Medicaid pharmacy files were used to identify prescriptions of metronidazole filled by mothers of the cohort children. | ||||||||
|
Zagorodnikova 2017 |
USA Not specified. cohort |
The two databases: the Organization of Teratology Information Specialists national research database and the Californian Teratology Information Service research database. | Pregnancies exposed to metronidazole at any time after conception. |
unexposed, sick
Pregnancies not exposed to metronidazole (disease-controlled). |
1st and 2nd trimester, during pregnancy (anytime or not specified) | 219 / 682 | Study on the efficacy of azole in an obstetrical indication, including only the intrauterine deaths and/or late pregnancy and/or neonatal outcomes that are studied as efficacy criteria rather than safety one. => Not reported here. | |
| Not specified. | ||||||||
| Study | Country Study period Study design |
Data source | Case | Control | Exposition | Exposition period | Sample size (exposed/unexposed) Or (case / control) |
Remarks | Risk of bias |
|---|---|---|---|---|---|---|---|---|---|
|
Abdel-Salam (All routes) 2000 |
Hungary 1980 - 1996 case control |
The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA). | Newborn infants (including infant deaths and usual stillborn fetuses) with isolated microcephaly. | Newborn infants (including infant deaths and usual stillborn fetuses) without congenital abnormalities. | 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. | during pregnancy (anytime or not specified) | 109 / 218 | Study design completed with other studies published on the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA). | |
| The Hungarian Congenital Abnormality Registry (HCAR), in which notification by physicians of cases with Congenital anomalies is mandatory (including infant deaths and usual stillborn fetuses). Controls were selected from the National Birth Registry of the Central Statistical Office. | |||||||||
|
Alexander 2001 |
Italy, Greece, Egypt, Brazil, Chile, mainland China, Hong Kong, and Japan. Not specified case control |
An international collaboration for a pilot case-control study of Infant acute leukemia (IAL). | Infant <18 months of age diagnosed with acute leukemia (IAL) in defined time periods and geographical areas. | Inpatients and outpatients at the same or similar hospitals without acute leukemia. | Maternal exposure data were obtained by interviews using a structured questionnaire. A pharmacist (blind to numbers of mothers and status) reviewed the list of medications reported by the mothers, but none were recognized as known topo-II inhibitors. | 3 months (or more) before pregnancy or during pregnancy | 136 / 266 | ||
| Case ascertainment was based on referrals to treating hospitals but was population based. | |||||||||
|
Caro-Paton 1997 |
Spain 1976 - 1993 case control |
Unpublished data collected by the Spanish Collaborative Study of Congenital Malformations (ECEMC, Estudio Colaborativo Espanol de Malformaciones Congenitas), a member of the European Network of Teratology Information (ENTIS). | New-borns with malformations. | Healthy new-borns, defined as the next new-born to a malformed child, with the same sex and born in the same hospital. | Maternal drug use was assessed by the attendant doctor during an interview with the mothers carried out within the first 3 days of delivery. | 1st trimester | 21078 / 20784 | Unpublished case-control study provided in the Meta-analysis published by Caro-Paton 1997. | |
| Not specified. | |||||||||
|
Czeizel 1998 |
Hungary 1980 - 1991 case control |
Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) | Cases of congenital abnormality from the information reported to the Registry. Exclusions included some mild congenital abnormalities, minor variants, and congenital abnormality syndromes of known origin. | Newborn infants without congenital abnormalities from the national birth registry of the Central Statistical Office. | 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. | 1st trimester | 17300 / 30663 | Overlapping: Medveczky 2004 studied specifically neural tube defects on the same database and on a longer period (1980 - 1996) => this outcome is not reported here. | |
| The Hungarian Congenital Abnormality Registry (HCAR), in which notification by physicians of cases with Congenital anomalies is mandatory. | |||||||||
|
Medveczky 2004 |
Hungary 1980 - 1996 case control |
The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA). | Newborn infants (including infant deaths and usual stillborn fetuses) with Neural tube defects with non-syndromic (i.e. isolated anencephaly, spina bifida aperta/cystica, encephalocele). | Newborn infants (including infant deaths and usual stillborn fetuses) without congenital abnormalities. | 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. | 1st trimester | 1202 / 38151 | Study design completed with other studies published on the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA). | |
| The Hungarian Congenital Abnormality Registry (HCAR), in which notification by physicians of cases with Congenital anomalies is mandatory (including infant deaths and usual stillborn fetuses). Controls were selected from the National Birth Registry of the Central Statistical Office. | |||||||||
|
Muanda b (Controls exposed to penicillins) 2017 |
Canada 1998 - 2009 nested case control |
The Quebec Pregnancy Cohort, an ongoing population-based cohort with prospective data collection. | Pregnancies with a diagnosis or procedure related to spontaneous abortion before the 20th week of gestation using diagnostic codes of the International Classification of Diseases. Only women with clinically detected spontaneous abortion were considered. | Pregnancies without a diagnosis or procedure related to spontaneous abortion before the 20th week of gestation using diagnostic codes of the International Classification of Diseases. | The province’s Public Prescription Drug Insurance Plan database (drug name, start date, dosage and duration). | during pregnancy (anytime or not specified) | 8702 / 87020 | Number of cases and controls. | |
| Régie de l’assurance maladie du Québec (RAMQ (diagnoses, medical procedures...), the provincial hospital discharge database (MEDÉCHO) (in-hospital diagnoses and procedures, and gestational age) and the Institut de la statistique du Quebec (birth weight). | |||||||||
|
Muanda b (Controls unexposed, NOS) 2017 |
Canada 1998 - 2009 nested case control |
The Quebec Pregnancy Cohort, an ongoing population-based cohort with prospective data collection. | Pregnancies with a diagnosis or procedure related to spontaneous abortion before the 20th week of gestation using diagnostic codes of the International Classification of Diseases. Only women with clinically detected spontaneous abortion were considered. | Pregnancies without a diagnosis or procedure related to spontaneous abortion before the 20th week of gestation using diagnostic codes of the International Classification of Diseases. | The province’s Public Prescription Drug Insurance Plan database (drug name, start date, dosage and duration). | during pregnancy (anytime or not specified) | 8702 / 87020 | Number of cases and controls. | |
| Régie de l’assurance maladie du Québec (RAMQ (diagnoses, medical procedures...), the provincial hospital discharge database (MEDÉCHO) (in-hospital diagnoses and procedures, and gestational age) and the Institut de la statistique du Quebec (birth weight). | |||||||||
|
Pombo-de-Oliveira 2006 |
Brazil 1999 - 2005 case control |
The Brazilian Collaborative Study Group of Infant Acute Leukemia who enrolled patients of 15 institutions in different cities of Brazil. | Children diagnosed with acute lymphoblastic leukemia or acute myelogenous leukemia at age <= 21 months and for which bone marrow aspirates were available for immunophenotyping and molecular analysis. | Children hospitalized in the same regional hospitals for an other medical reason than Infant Acute Leukemia. | Mothers were interviewed in person in the hospital with the aid of a well-structured questionnaire divided in two major sections, from which one related to exposures during pregnancy. | during pregnancy (anytime or not specified) | 202 / 440 | ||
| Mothers were interviewed in person in the hospital with the aid of a well-structured questionnaire divided in two major sections. The first part of the questionnaire was devoted to childbirth and nursing. | |||||||||
|
Rosa 1987 |
USA 1980 - 1983 case control |
COMPASS, a database generated by Health Information Designs from routinely computerized Medicaid invoices for prescriptions and diagnoses | Patients aged zero to four years with suspected birth defect diagnoses, pregnancies ending in spontaneous abortions (ICD9 634-634.9). | Deliveries not linked to birth defects. | Medicaid invoices for prescriptions. | 1st trimester, 3 months (or more) before pregnancy or during pregnancy | 6564 / 97775 | Study on the efficacy of azole in an obstetrical indication, including the intrauterine deaths and/or late pregnancy and/or neonatal outcomes that are studied as efficacy criteria rather than safety one. => Not reported here. | |
| Medicaid invoices for diagnoses. | |||||||||
|
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.v | |||||||||
|
Santos 2011 |
Canada 1998 - 2003 nested case control |
The Québec Pregnancy Registry, built from the linkage of three administrative databases. | A pregnancy resulting in small-for-gestational-age (SGA) newborn, that weighed less than the tenth percentile according to the Canadian gender specific reference curves. | A pregnancy resulting in a newborn that weighed greater or equal to the tenth percentile. | The Régie de l’assurance maladie du Québec (RAMQ) database, that provides information on prescriptions filled for residents insured by Québec’s Public Drug Insurance Plan. Data are available for physician-based diagnoses, therapeutic procedures, characteristics of patient, and healthcare providers. | 2nd and/or 3rd trimester | 8192 / 55146 | ||
| The Med-Echo database that records hospitalisation data such as gestational age for deliveries for all Quebec residents. It also records the gestational age for planned abortions, miscarriages, and deliveries. | |||||||||
|
Santos 2012 |
Canada 1998 - 2002 nested case control |
The Québec Pregnancy Registry, built from the linkage of three administrative databases. | Pregnant women who delivered before the 37th week of gestation. | Pregnant women who delivered term babies. | The Régie de l’assurance maladie du Québec (RAMQ) database, that provides information on prescriptions filled for residents insured by Québec’s Public Drug Insurance Plan. Data are available for physician-based diagnoses, therapeutic procedures, characteristics of patient, and healthcare providers. | 2nd and/or 3rd trimester | -9 / -9 | Methods and Risk of Bais (ROB) completed with Santos et al. 2011. Number of cases and controls not provided. | |
| The Med-Echo database that records hospitalisation data such as gestational age for deliveries for all Quebec residents. It also records the gestational age for planned abortions, miscarriages, and deliveries. | |||||||||
|
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. | |||||||||
|
Wright 2012 |
Canada 2008 - 2010 case control |
High-risk perinatal unit of Mount Sinai Hospital, Toronto, Canada, is a tertiary-care referral center. | Neonates with antibiotic resistance in early-onset neonatal sepsis (EOS). | Neonates with antibiotic susceptibility in early-onset neonatal sepsis (EOS). | Medical information including antibiotic use were abstracted from hospital charts. Mothers were telephoned to confirm antibiotic exposure and to obtain consent to contact obstetrical care providers to validate antibiotic use data. | during pregnancy (anytime or not specified) | 32 / 28 | ||
| Medical information were abstracted from hospital charts. | |||||||||
Risk of bias: : NA; : low; : moderate; : serious; : critical; : unclear;
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