Metronidazole (all routes except local only) - Medication and Pregnancy KB

Metronidazole (all routes except local only)

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Andrews, 2003	USA 1996 - 2000	Asymptomatic pregnant women with a positive cervical or vaginal fetal fibronectin test before 26 weeks’ gestation.	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.	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.
Diav-Citrin, 2001	Israel 1989 - 1998	All women who contacted (directly or through their health care providers) the Israeli TIS during those years for information about gestational exposure to metronidazole or to nonteratogenic agents.	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.	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.
Heinonen (Controls exposed to penicillins), 1977	USA 1959 - 1965	Pregnant women admitted to collaborating hospital clinics.	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).	31 / 3546
Heinonen (Controls unexposed, NOS), 1977	USA 1959 - 1965	Pregnant women admitted to collaborating hospital clinics.	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.	31 / 50251
Jeffcoat, 2003	USA Not specified	Pregnant women with periodontitis recruited were between 21 and 25 weeks’ gestation and screened for at least three sites with clinical attachment loss ≥3 mm.	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.	120 / 123
Kamal, 2018	Egypt 2014 - 2015	Pregnant women with gestational age of 20-36 weeks with no medical risk factors of preterm labour birth.	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.	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.
Koss, 2012	USA 2000 - 2002	Pregnant women residing in central Syracuse ZIP codes who presented for delivery hospital for Syracuse, New York.	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.	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.'
Mann, 2009	USA 1996 - 2002	Singleton live births in South Carolina from 1996 through 2002 identified in the Medicaid billing 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.	-9 / -9
Morgan, 1978	England 1971 - 1976	Patients with trichomoniasis in pregnancy who delivered at Hammersmith Hospital.	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.	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.
Muanda a (Controls exposed to penicillins), 2017	Canada 1998 – 2008	All pregnancies ending with a live-born singleton with a continuous prescription drug insurance coverage of ≥12 months before the first day of gestation, during pregnancy and with at least 12 months of follow-up after birth.	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.	412 / 9106	Pregnancies with exposure to known teratogens during the first trimester, chromosomal aberrations and minor malformations were also excluded.
Muanda a (Controls unexposed, NOS), 2017	Canada 1998 - 2008	All pregnancies ending with a live-born singleton whose mothers were covered by the “Régie de l’assurance maladie du Québec” drug plan.	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.	412 / 124469
Piper, 1993	USA 1983 - 1988	Pregnant women 15-44 years of age were identified from 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.	1307 / 1311	Minor abnormalities and conditions that were recorded inconsistently in delivery facilities were not considered birth defects.
Sorensen, 1999	Denmark 1991 - 1996	Pregnant women identified from the Danish Medical Birth Registry.	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.	124 / 13327
Thapa, 1998	USA 1975 - 1992	Children younger than 5 years, born to women enrolled in Tennessee Medicaid during their pregnancy, who were exposed and unexposed to metronidazole in utero.	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.	79716 / 1092980	Number of exposed and unexposed in person-years.
Zagorodnikova, 2017	USA Not specified.	Pregnant patients with infections of genitourinary tract that called one of the Teratology Information Service (TIS).	Pregnancies exposed to metronidazole at any time after conception.	unexposed, sick Pregnancies not exposed to metronidazole (disease-controlled).	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.

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk
Abdel-Salam (All routes), 2000	Hungary 1980 - 1996	Newborn infants (including infant deaths and usual stillborn fetuses) with isolated microcephaly.	Newborn infants (including infant deaths and usual stillborn fetuses) without congenital abnormalities.	109 / 218	Study design completed with other studies published on the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA).
Alexander, 2001	Italy, Greece, Egypt, Brazil, Chile, mainland China, Hong Kong, and Japan. Not specified	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.	136 / 266
Caro-Paton, 1997	Spain 1976 - 1993	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.	21078 / 20784	Unpublished case-control study provided in the Meta-analysis published by Caro-Paton 1997.
Czeizel, 1998	Hungary 1980 - 1991	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.	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.
Medveczky, 2004	Hungary 1980 - 1996	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.	1202 / 38151	Study design completed with other studies published on the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA).
Muanda b (Controls exposed to penicillins), 2017	Canada 1998 - 2009	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.	8702 / 87020	Number of cases and controls.
Muanda b (Controls unexposed, NOS), 2017	Canada 1998 - 2009	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.	8702 / 87020	Number of cases and controls.
Pombo-de-Oliveira, 2006	Brazil 1999 - 2005	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.	202 / 440
Rosa, 1987	USA 1980 - 1983	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.	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.
Ross, 2003	USA and Canada 1983 - 1988	Children diagnosed with acute leukemia (i.e., acute myeloid leukemia, AML and acute lymphoblastic leukemia, ALL) in the first 18 months of life.	Children without leukemia identified through random digit dialing.	243 / 393
Santos, 2011	Canada 1998 - 2003	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.	8192 / 55146
Santos, 2012	Canada 1998 - 2002	Pregnant women who delivered before the 37th week of gestation.	Pregnant women who delivered term babies.	-9 / -9	Methods and Risk of Bais (ROB) completed with Santos et al. 2011. Number of cases and controls not provided.
Werler, 2014	USA 2007 - 2011	All infants less than 11 months of age with a diagnosis of talipes equinovarus or clubfoot (without a known chromosomal anomaly, inherited syndrome, bilateral renal agenesis, Potter syndrome, or neural tube defect).	Random samples of children born in the same years as cases but without known malformations.	646 / 2037	'On the basis of the timing of clubfoot development, the exposure window of interest is lunar months (LMs) 2–4, which is 29–112 days after the first day of the last menstrual period.'
Wright, 2012	Canada 2008 - 2010	Neonates with antibiotic resistance in early-onset neonatal sepsis (EOS).	Neonates with antibiotic susceptibility in early-onset neonatal sepsis (EOS).	32 / 28

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