Anti-infective/Amebicide/Trichomonacide
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Hold Breastfeeding (Single Dose) Limited Human Data—Potential Toxicity (Divided Dose)
PREGNANCY SUMMARY
Although some of the available reports have arrived at conflicting conclusions as to the safety of metronidazole in pregnancy, most of the published evidence suggests that the anti-infective does not represent a significant risk of structural defects to the fetus. At present, it is not possible to assess the risk to the fetus from the carcinogenic potential of metronidazole. The answer to the question of transplacental carcinogenic potential of metronidazole has major public health implications, but may never be answered because of the rarity of childhood cancers and the inability to identify potentially confounding environmental factors in older children and adults. The manufacturer considers metronidazole to be contraindicated during the 1st trimester in patients with trichomoniasis or bacterial vaginosis (1). The use of metronidazole for trichomoniasis or vaginosis during the 2nd and 3rd trimesters is acceptable. For other indications, metronidazole can be used during pregnancy if there are no other alternatives with established safety profiles.
FETAL RISK SUMMARY
Metronidazole possesses trichomonacidal and amebicidal activity as well as effectiveness against certain bacteria. The drug crosses the placenta to the fetus throughout gestation with a cord:maternal plasma ratio at term of approximately 1.0 (2–4). The pharmacokinetics of metronidazole in pregnant women has been reported (5,6).
Reproduction studies conducted in mice (at oral doses about 0.1 times the human dose) and in rats (at doses up to 5 times the human dose) revealed no fetal harm. After intraperitoneal administration in mice, however, some fetal deaths were noted (1).
The use of metronidazole in pregnancy is controversial. The drug is mutagenic in bacteria and carcinogenic in rodents, and although these properties have never been shown in humans, concern for these toxicities have led some to advise against the use of metronidazole in pregnancy (7,8). However, no association with human cancer has been proven (8,9).
A 1995 case report described a 32-year-old woman who was treated with metronidazole during the 12th and 13th weeks of pregnancy with 500 mg/day orally plus 500 mg/day intravaginally for 10 days (10). She eventually delivered an apparently normal, 3640-g male infant at term. Fifteen days later, the infant was diagnosed with adrenal neuroblastoma with hepatic metastasis (eventual outcome not mentioned). The authors acknowledged that neuroblastoma was the second most common malignant solid tumor in childhood and that a causal relationship between the tumor and metronidazole in this case could not be established (10).
A retrospective cohort study of childhood cancer and in utero exposure to metronidazole was reported in 1998 (11). The cohort included 328,846 children under 5 years of age who had been born to women (ages 15–44 years) enrolled from 1975 through 1992 in Tennessee Medicaid at any time between the last menstrual period and the date of delivery. Exposure to metronidazole was based on Medicaid pharmacy prescription records. A statewide childhood cancer database was developed to identify study cases. In the cohort, 8.1% were exposed in utero to metronidazole and 91.9% were not exposed. From 952 children younger than 5 years of age in the cancer database, 175 met the criteria for the study (first primary cancer before age 5 years, a Tennessee resident, and seen at a Tennessee hospital at the time of diagnosis). The study was limited to children under the age of 5 years to minimize the loss to out-of-state migration (expected to be no more than 6% (12)). None of the study cases had a history of therapeutic radiation or exposure to chemotherapy before their cancer diagnosis. The cancer type, number of cases, adjusted relative risk (RR), and 95% confidence interval (CI) were, for all cancers: N = 175, RR 0.81, 95% CI 0.41–1.59; for leukemia: N = 42, no exposed cases; for central nervous system tumors: N = 30, RR 1.23, 95% CI 0.29–5.21; for neuroblastoma: N = 28, RR 2.60, 95% CI 0.89–7.59; and other cancers: N = 75, RR 0.57, 95% CI 0.18–1.82. Although none of the observed relative risks were statistically significant, the authors stated that the increased risk for neuroblastoma needed further evaluation (11).
In a brief comment, other investigators agreed with the conclusions of the above study but expressed concern that the frequent use of medications during pregnancy combined with the rarity of childhood cancer made it difficult to establish a carcinogenic effect (12). In addition, limiting the study to children less than 5 years of age prevented the identification of potential effects on later developing cancers such as Hodgkin’s disease, Ewing’s sarcomas, and osteosarcoma.
Several studies, individual case reports, and reviews have described the safe use of metronidazole during pregnancy (13–27). Included among these is a 1972 review summarizing 20 years of experience with the drug and involving 1469 pregnant women, 206 of whom were treated during the 1st trimester (27). No association with congenital malformations, abortions, or stillbirths was found. Some investigations, however, found an increased risk when the agent was used early in pregnancy (9,28–30).
In a 1979 report, metronidazole was used in 57 pregnancies including 23 during the 1st trimester (9). Three of the 1st trimester exposures ended in spontaneous abortion (a normal incidence), and in the remaining 20 births, there were 5 congenital anomalies: hydrocele (two), congenital dislocated hip (female twin), metatarsus varus, and mental retardation (both parents mentally slow). Analysis of the data is not possible because of the small numbers and possible involvement of genetic factors (9).
The Collaborative Perinatal Project monitored 50,282 mother–child pairs, 31 of whom had 1st trimester exposure to metronidazole (28). A possible association with malformations was found (RR 2.02) based on defects in four children, but independent confirmation is required.
Two mothers, treated with metronidazole during the 5th–7th weeks of gestation for amebiasis, gave birth to infants with midline facial defects (29). Diiodohydroxyquinoline was also used in one of the pregnancies. One of the infants had holotelencephaly and one had unilateral cleft lip and palate.
A mother treated for trichomoniasis between the 6th and 7th weeks of gestation gave birth to a male infant with a cleft of the hard and soft palate, optic atrophy, a hypoplastic, short philtrum, and a Sydney crease on the left hand (30). The mother was also taking an antiemetic medication (Bendectin) on an “as needed” basis. Chromosomal analysis of the infant was normal. The relationship between metronidazole and the defects is unknown.
As of May 1987, the FDA had received reports of 26 adverse outcomes with metronidazole: spontaneous abortions (N = 3), brain defects (N = 6), limb defects (N = 5), genital defects (N = 3), unspecified defects (N = 3), and 1 each of craniostenosis, peripheral neuropathy, ventricular septal defect, retinoblastoma, obstructive uropathy, and a chromosomal defect (31). In this same report, the authors, from data obtained from the Michigan Medicaid program between 1980 and 1983, cited 1020 other cases in which metronidazole use in the 1st trimester for treatment of vaginitis was not linked with birth defects. In an additional 63 cases, use of the agent for this indication was linked to a birth defect diagnosis. Based on these data, the estimated RR of a birth defect was 0.92 (95% CI 0.7–1.2). Of the 122 infants with oral clefts, none was exposed to metronidazole. An estimated RR for spontaneous abortion of 1.67 (95% CI 1.4–2.0) was determined from 135 exposures among 4264 spontaneous abortions compared to 1020 exposures among 55,736 deliveries (31).
In a continuation of the study cited immediately above, 229,101 completed pregnancies of Michigan Medicaid recipients were evaluated between 1985 and 1992 (F. Rosa, personal communication, FDA, 1993). Of this group, 2445 newborns had been exposed to metronidazole during the 1st trimester. A total of 100 (4.1%) major birth defects were observed (97 expected). Specific data were available for six defect categories, including (observed/expected) 23/24 cardiovascular defects, 1/1 spina bifida, 4/7 polydactyly, 2/4 limb reduction defects, 7/6 hypospadias, and 8/4 oral clefts. Only with oral clefts is there a suggestion of a possible association, but in view of the outcomes observed between 1980 and 1983, other factors, such as the mother’s disease, concurrent drug use, and chance, are probably involved.
Using data from the Tennessee Medicaid program, pregnancy outcomes of women (N = 1307) who had filled a prescription for metronidazole between 30 days before and 120 days after the onset of their last normal menstrual period were compared with those of women who had not filled such a prescription (32). The groups were matched for age, race, year of delivery, and hospital. Data were available for 1322 exposed (1318 live births; 4 stillbirths) and 1328 nonexposed (1320 live births; 8 stillbirths) infants. The occurrence of birth defects was similar in the two groups; 96 in the exposed group and 80 in the nonexposed group (adjusted odds ratio [OR] 1.2; 95% CI 0.9–1.6). Similar results were obtained when congenital malformations were analyzed by specific types, including those of the central nervous system, heart, gastrointestinal tract, musculoskeletal system, urogenital system, respiratory tract, chromosomal, and by multiple organ systems. The investigators concluded that the use of metronidazole was not associated with an increased risk for birth defects (32).
A study published in 1995 conducted a meta-analysis of seven studies (from a total of 32 references identified in their search) that met their criteria for assessing the safety of metronidazole use in human pregnancy (33). The criteria required exposure during the 1st trimester and comparison of these outcomes with the outcomes of pregnancies that were not exposed or only exposed during the 3rd trimester. Six of the studies were prospective and one was retrospective. The OR (exposure vs. no exposure during the 1st trimester) for the seven studies was 0.93 (95% CI 0.73–1.18) and for the six prospective studies was 1.02 (95% CI 0.48–2.18). Based on these findings, the investigators concluded that the use of metronidazole during the 1st trimester was not associated with an increased risk of congenital defects (33).
A second meta-analysis, similar in design to the study above, evaluated the risk for birth defects after the use of metronidazole early in pregnancy (34). A total of five studies, one unpublished case–control study and four published cohort studies, met the inclusion criteria. As in the study immediately above, the OR 1.08 (95% CI 0.90–1.29) indicated that exposure to metronidazole during the 1st trimester was not associated with birth defects (34).
A large ethnically homogeneous population-based dataset (Hungarian Case–Control Surveillance of Congenital Abnormalities, 1980–1991) was used in a study published in 1998 to evaluate whether the use of metronidazole in the 1st trimester was associated with congenital anomalies (35). The background rate of congenital malformations in the dataset was 4.0%–4.7% (liveborn, stillborn, and selectively terminated fetuses). Minor abnormalities and congenital abnormality syndromes of known origin were excluded. Among 17,300 cases with birth defects, 665 (3.8%) were treated with metronidazole (oral and IV) in the 2nd to 3rd months of gestation (dating from last menstrual period). In comparison, among 30,663 matched controls, 1041 (3.4%) were treated with metronidazole (oral and IV) during this period of gestation. Using the McNemar analysis of case–control pairs, the only defect with a positive association was cleft lip ± palate (nine cases) (adjusted OR 8.54, 95% CI 1.06–68.86). The investigators concluded that the most likely reasons for the association were recall bias or chance alone, but that a true association could not be ruled out. However, based on the prevalence of isolated cleft lip (with or without cleft palate) in their population and the prevalence of exposure to metronidazole during the 2nd and 3rd months of pregnancy, their analysis suggested that even a true association would only increase the prevalence of the defect from 100 cases/100,000 births to 103 cases/100,000 births. Moreover, the finding was not confirmed when the comparison was made with the total control group (35).
In a second study from the above group, the teratogenic potential of vaginal metronidazole plus miconazole treatment during the 2nd and 3rd months of pregnancy was evaluated using the 1980–1996 dataset of the Hungarian Case–Control Surveillance of Congenital Abnormalities (36). Their analysis included 21 groups of congenital anomalies. They compared 22,843 women who had newborn infants or fetuses with congenital anomalies (cases) with 38,151 pregnant women who had newborns without defects (controls). Vaginal treatment with the drug combination occurred in 2.5% (576) cases and 2.2% (846) controls. The analysis of cases and their matched controls found an association between the drug combination and polysyndactyly (21 cases) with an adjusted prevalence OR 6.0, 95% CI 2.4–15.2. The authors thought that recall bias was unlikely and considered their findings to be a signal of the defect, although they had no plausible biological mechanism (36).
A population-based cohort study on the use of metronidazole during pregnancy from 1991 to 1996 was conducted in Denmark and reported in 1999 (37). An estimated 35,000 pregnancies were used in the risk analysis for the specific outcomes of congenital abnormalities, low birth weight (<2500 g), and preterm birth (<37 weeks). Data on the use of metronidazole were determined from a prescription database and classified as either exposure from 30 days before conception to the end of the 1st trimester (group 1) or during the 2nd and 3rd trimesters (group 2). A total of 138 prescriptions to the agent were obtained by 124 women during the study period. A control group of 13,327 pregnancies was used for comparison. Outcome data were determined independently from exposure information. Based on prevalence rates of congenital anomalies in the exposed (group 1) and control groups of 2.4% and 5.2%, respectively, no increased risk for malformations was found (OR 0.44, 95% CI 0.11–1.81). The two birth defects in group 1 were transposition vasorum with ventricular septum defect and hypertelorism. Preterm birth occurred in 6 of the 124 exposed women (4.8%) and in 793 of 13,327 controls (6.0%) (adjusted OR 0.80, 95% CI 0.35–1.83). After adjustment for maternal age, birth order, gestational age, and smoking, there was no difference in mean birth weight between those exposed and the controls. The investigators acknowledged the major limitations of their study: low statistical power due to the small number of exposed subjects; the inability to control for potentially confounding factors; and the lack of information on spontaneous abortions and fetuses aborted for prenatal diagnosis of malformations. They concluded, however, that their results showed no evidence of major teratogenicity and no indication for the termination of pregnancies because of exposure to metronidazole (37).
Metronidazole has been shown to markedly potentiate the fetotoxicity and teratogenicity of alcohol in mice (38). Human studies of this possibly clinically significant interaction have not been reported.
A 2001 prospective, controlled cohort study evaluated the pregnancy outcomes of 217 women exposed to metronidazole (86.2% exposed in 1st trimester) (39). The women had consulted a Teratogen Information Service concerning their exposure to the drug. A matched control group consisted of 612 women who had called about nonteratogenic exposures. There were no statistical differences between the groups in terms of spontaneous abortions (7.8% vs. 7.2%), stillbirths (0.0% vs. 0.2%), preterm delivery (6.8% vs. 5.7%), or rate of major birth defects (2.6% vs. 2.1%). However, exposed cases had a lower birth weight than controls (3253 vs. 3375 g, p = 0.004) (39).
A number of reports have described the use of metronidazole in pregnant women with bacterial vaginosis in attempts to reduce the incidence of preterm births (40–50). A 1994 randomized, double-blind, placebo-controlled study found that two courses of oral metronidazole (400 mg twice daily for 2 days) administered at 24 and 29 weeks’ gestation, respectively, were effective in suppressing Gardnerella vaginalis for 2–3 months in the majority of women with bacterial vaginosis (40).
A prospective, randomized, double-blind, placebo-controlled study first published in abstract form in 1993 (41) and then in full in 1994 (42) compared a 7-day course of oral metronidazole (750 mg/day) to a 7-day course of placebo in women with bacterial vaginosis and a history of preterm birth (<37 weeks’ gestation) in the preceding pregnancy from either idiopathic preterm labor or premature rupture of membranes. The women were enrolled between 13 and 20 weeks’ gestation. Compared to the placebo group (N = 36), the pregnancy outcomes of the active drug group (N = 44) included significantly fewer admissions for preterm labor (27% vs. 78%, p <0.05), fewer preterm births (18% vs. 39%, p <0.05), fewer newborns with birth weight <2500 g (14% vs. 33%, p <0.05), and fewer cases of premature rupture of membranes (5% vs. 33%, p <0.05) (42).
Another prospective randomized, double-blind, placebo-controlled study first published in abstract form in 1993 (43) and then in full in 1995 (44) described the effect of a 7-day course of oral metronidazole (750 mg/day) combined with a 14-day course of oral erythromycin base (999 mg/day) in pregnant women at increased risk for preterm delivery (based on a history of spontaneous preterm delivery or prepregnancy body weight less than 50 kg). At enrollment (at a mean 23 weeks’ gestation for both groups), 41% of the 433 women in the active drug group had bacterial vaginosis compared with 46% of the 191 women receiving placebo. If a second examination (at a mean 27.6 weeks’ gestation for both groups) revealed bacterial vaginosis, a second course of active drugs or placebo was administered. Eight women were lost to follow-up. A total of 110 women (26%) in the active group delivered preterm (<37 weeks) compared with 68 women (36%) in the placebo group (p = 0.01). However, the rates of preterm delivery in those without bacterial vaginosis were nearly identical (22% in the active drug group vs. 25% in the placebo group, p = 0.55). In contrast, in those with bacterial vaginosis, the rates of preterm delivery were 31% for the active drug group compared with 49% in those receiving placebo, p = 0.006. The positive association with anti-infective treatment existed both for women with a history of preterm birth (39% vs. 57%, p = 0.02) and prepregnancy body weight less than 50 kg (14% vs. 33%, p = 0.04) (44).
A 1997 randomized, placebo-controlled study also found that the beneficial effect of a 2-day course of oral metronidazole (400 mg twice daily) on prolonging pregnancy was restricted to those women with bacterial vaginosis and a previous history of spontaneous preterm birth (45). Metronidazole therapy was started at 24 weeks’ gestation and repeated at 29 weeks’ if G. vaginalis was still present.
Another 1997 randomized, double blind, placebo-controlled study administered a combination of metronidazole and ampicillin to 59 women and placebo to 51 women (46). The subjects in both groups had threatened idiopathic preterm labor and intact membranes. The anti-infective regimen was an 8-day course of metronidazole (500 mg IV every 8 hours for 24 hours, then 400 mg orally every 8 hours for 7 days) and ampicillin (2 g IV every 6 hours for 24 hours, then pivampicillin 500 mg orally every 8 hours for 7 days). The women were enrolled in the study at 26–34 weeks’ gestation from six clinics in the Copenhagen area. Treatment with the anti-infectives was associated with prolongation of gestation (47.5 vs. 27 days, p <0.05), higher gestational age at birth (37 vs. 34 weeks, p <0.05), reduced preterm birth rate (40% vs. 63%, p <0.05), and a lower rate of admission to neonatal intensive care unit (40% vs. 63%, p <0.05). The incidences of maternal (5% vs. 0%, p = 0.30) and neonatal (10% vs. 22%, p = 0.18) infectious morbidity, however, were statistically similar between the groups (46). In four other reports, all from the same source, gestational metronidazole treatment of women with asymptomatic bacterial vaginosis, but without a history of previous preterm birth, either did not reduce the risk of preterm birth (47–49) or increased the risk for that outcome (50).
Metronidazole was not effective in preventing preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection in a 2001 report (51). Women were screened for the infection at 16–23 weeks’ gestation and then randomized to either metronidazole (N = 320) or placebo (N = 297). The metronidazole group received two 2-g doses 48 hours apart at randomization and then again at 24–29 weeks’. Preterm delivery (<37 weeks’) occurred in 19% of the treated group and about 11% of the controls (51).
BREASTFEEDING SUMMARY
Metronidazole is excreted into breast milk. Following a single 2-g oral dose in three patients, peak milk concentrations in the 50–60 mcg/mL range were measured at 2–4 hours (52). With normal breastfeeding, infants would have received about 25 mg of metronidazole during the next 48 hours. By interrupting feedings for 12 hours, infant exposure to the drug would have been reduced to 9.8 mg, or 3.5 mg if feeding had been stopped for 24 hours (52).
In women treated with divided oral doses of either 600 or 1200 mg/day, the mean milk levels were 5.7 and 14.4 mcg/mL, respectively (53). The milk:plasma ratios in both groups were approximately 1.0. The mean plasma concentrations in the exposed infants were about 20% of the maternal plasma drug level. Eight women treated with metronidazole rectal suppositories, 1 g every 8 hours, produced a mean milk drug level of 10 mcg/mL with maximum concentrations of 25 mcg/mL (54).
One report described diarrhea and secondary lactose intolerance in a breastfed infant whose mother was receiving metronidazole (55). The relationship between the drug and the events is unknown. Except for this one case, no reports of adverse effects in metronidazole-exposed nursing infants have been located. However, because the drug is mutagenic and carcinogenic in some test species (see Fetal Risk Summary), unnecessary exposure to metronidazole should be avoided. However, topical or vaginal use of metronidazole during breastfeeding does not appear to represent a risk to a nursing infant.
A 1988 report analyzed the milk and plasma concentrations of metronidazole and its metabolite (hydroxymetronidazole) in 12 breastfeeding women who had been taking 400 mg 3 times daily for 4 days (56). The mean milk:plasma ratios for the parent drug and metabolite were 0.9 and 0.76, respectively. In seven of the nursing infants, the plasma concentrations for the parent drug and metabolite ranged from 1.27 to 2.41 mcg/mL and 1.1 to 2.4 mcg/mL, respectively. The investigators also monitored 35 other women under treatment with metronidazole while nursing. There were no significant increases in adverse effects in their infants that could be attributed to the drug therapy (56).
If a single, 2-g oral dose of metronidazole is used for trichomoniasis, the American Academy of Pediatrics recommends discontinuing breastfeeding for 12–24 hours to allow excretion of the drug (57).
References
1.Product information. Flagyl. G.D. Searle, 2000.
2.Amon K, Amon I, Huller H. Maternal-fetal passage of metronidazole. In Advances in Antimicrobial and Antineoplastic Chemotherapy. Proceedings of the VII International Congress of Chemotherapy, Prague, 1971:113–5.
3.Heisterberg L. Placental transfer of metronidazole in the first trimester of pregnancy. J Perinat Med 1984;12:43–5.
4.Karhunen M. Placental transfer of metronidazole and tinidazole in early human pregnancy after a single infusion. Br J Clin Pharmacol 1984;18:254–7.
5.Amon I, Amon K, Franke G, Mohr C. Pharmacokinetics of metronidazole in pregnant women. Chemotherapy 1981;27:73–9.
6.Visser AA, Hundt HKL. The pharmacokinetics of a single intravenous dose of metronidazole in pregnant patients. J Antimicrob Chemother 1984;13:279–83.
7.Anonymous. Is Flagyl dangerous? Med Lett Drugs Ther 1975;17:53–4.
8.Finegold SM. Metronidazole. Ann Intern Med 1980;93:585–7.
9.Beard CM, Noller KL, O’Fallon WM, Kurland LT, Dockerty MB. Lack of evidence for cancer due to use of metronidazole. N Engl J Med 1979;301:519–22.
10.Carvajal A, Sanchez A, Hurtarte G. Metronidazole during pregnancy. Int J Gynecol Obstet 1995;48:323–4.
11.Thapa PB, Whitlock JA, Brockman Worrell KG, Gideon P, Mitchel EF Jr, Roberson P, Pais R, Ray WA. Prenatal exposure to metronidazole and risk of childhood cancer. A retrospective cohort study of children younger than 5 years. Cancer 1998;83:1461–8.
12.Berbel-Tornero O, Lopez-Andreu JA, Ferris-Tortajada J. Prenatal exposure to metronidazole and risk of childhood cancer. A retrospective cohort study of children younger than 5 years. Cancer 1999;85:2494–5.
13.Gray MS. Trichomonas vaginalis in pregnancy: the results of metronidazole therapy on the mother and child. J Obstet Gynaecol Br Commonw 1961;68:723–9.
14.Robinson SC, Johnston DW. Observations on vaginal trichomoniasis. II. Treatment with metronidazole. Can Med Assoc J 1961;85:1094–6.
15.Luthra R, Boyd JR. The treatment of trichomoniasis with metronidazole. Am J Obstet Gynecol 1962;83:1288–93.
16.Schram M, Kleinman H. Use of metronidazole in the treatment of trichomoniasis. Am J Obstet Gynecol 1962;83:1284–7.
17.Andrews MC, Andrews WC. Systemic treatment of trichomonas vaginitis. South Med J 1963;56:1214–8.
18.Zacharias LF, Salzer RB, Gunn JC, Dierksheide EB. Trichomoniasis and metronidazole. Am J Obstet Gynecol 1963;86:748–52.
19.Kotcher E, Frick CA, Giesel LO, Jr. The effect of metronidazole on vaginal microbiology and maternal and neonatal hematology. Am J Obstet Gynecol 1964;88:184–9.
20.Scott-Gray M. Metronidazole in obstetric practice. J Obstet Gynaecol Br Commonw 1964;71:82–5.
21.Perl G. Metronidazole treatment of trichomoniasis in pregnancy. Obstet Gynecol 1965;25:273–6.
22.Peterson WF, Stauch JE, Ryder CD. Metronidazole in pregnancy. Am J Obstet Gynecol 1966;94:343–9.
23.Robinson SC, Mirchandani G. Trichomonas vaginalis. V. Further observations on metronidazole (Flagyl) (including infant follow-up). Am J Obstet Gynecol 1965;93:502–5.
24.Mitchell RW, Teare AJ. Amoebic liver abscess in pregnancy. Case reports. Br J Obstet Gynaecol 1984;91:393–5.
25.Morgan I. Metronidazole treatment in pregnancy. Int J Gynaecol Obstet 1978;15:501–2.
26.Sands RX. Pregnancy, trichomoniasis, and metronidazole. Am J Obstet Gynecol 1966;94:350–3.
27.Berget A, Weber T. Metronidazole and pregnancy. Ugeskr Laeger 1972;134:2085–9. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:426.
28.Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977:298, 299, 302.
29.Cantu JM, Garcia-Cruz D. Midline facial defect as a teratogenic effect of metronidazole. Birth Defects 1982;18:85–8.
30.Greenberg F. Possible metronidazole teratogenicity and clefting. Am J Med Genet 1985;22:825.
31.Rosa FW, Baum C, Shaw M. Pregnancy outcomes after first-trimester vaginitis drug therapy. Obstet Gynecol 1987;69:751–5.
32.Piper JM, Mitchel EF, Ray WA. Prenatal use of metronidazole and birth defects: no association. Obstet Gynecol 1993;82:348–52.
33.Burtin P, Taddio A, Ariburnu O, Einarson TR, Koren G. Safety of metronidazole in pregnancy: a meta-analysis. Am J Obstet Gynecol 1995;172:525–9.
34.Caro-Paton T, Carvajal A, Martin de Diego I, Martin-Arias LH, Alvarez Requejo A, Rodriguez Pinilla E. Is metronidazole teratogenic? A meta-analysis. Br J Clin Pharmacol 1997;44:179–82.
35.Czeizel AE, Rockenbauer M. A population based case-control teratologic study of oral metronidazole treatment during pregnancy. Br J Obstet Gynaecol 1998;105:322–7.
36.Kazy Z, Puho E, Czeizel AE. The possible association between the combination of vaginal metronidazole and miconazole treatment and poly-syndactyly population-based case-control teratologic study. Reprod Toxicol 2005;20:89–94.
37.Sorensen HT, Larsen H, Jensen ES, Thulstrup AM, Schonheyder HC, Nielsen GL, Czeizel A, and the EUROMAP Study Group. Safety of metronidazole during pregnancy: a cohort study of risk of congenital abnormalities, preterm delivery and low birth weight in 124 women. J Antimicrob Chemother 1999;44:854–5.
38.Damjanov I. Metronidazole and alcohol in pregnancy. JAMA 1986;256:472.
39.Diav-Citrin O, Shechtman S, Gotteiner T, Arnon J, Ornoy A. Pregnancy outcome after gestational exposure to metronidazole: a prospective controlled cohort study. Teratology 2001;63:186–92.
40.McDonald HM, O’Loughlin JA, Vigneswaran R, Jolley PT, McDonald PJ. Bacterial vaginosis in pregnancy and efficacy of short-course oral metronidazole treatment: a randomized controlled trial. Obstet Gynecol 1994;84:343–8.
41.Morales WJ, Schorr S, Albritton J. Effect of metronidazole in patients with history of preterm birth and bacterial vaginosis: a placebo control double blind study (abstract). Am J Obstet Gynecol 1993;168:377.
42.Morales WJ, Schorr S, Albritton J. Effect of metronidazole in patients with preterm birth in preceding pregnancy and bacterial vaginosis: a placebo-controlled, double-blind study. Am J Obstet Gynecol 1994;171:345–9.
43.Hauth J, Goldenberg R, Andrews W, Copper R, Schmid T. Efficacy of metronidazole plus erythromycin to decrease bacterial vaginosis and other markers of altered vaginal flora (abstract). Am J Obstet Gynecol 1993;168:421.
44.Hauth JC, Goldenberg RL, Andrews WW, DuBard MB, Copper RL. Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis. N Engl J Med 1995;333:1732–6.
45.McDonald HM, O’Loughlin JA, Vigneswaran R, Jolley PT, Harvey JA, Bof A, McDonald PJ. Impact of metronidazole therapy on preterm birth in women with bacterial vaginosis flora (Gardnerella vaginalis): a randomized, placebo controlled trial. Br J Obstet Gynaecol 1997;104:1391–7.
46.Svare J, Langhoff-Roos J, Andersen LF, Kryger-Baggesen N, Borch-Christensen H, Heisterberg L, Kristensen J. Ampicillin-metronidazole treatment in idiopathic preterm labour: a randomized controlled multicentre trial. Br J Obstet Gynaecol 1997;104:892–7.
47.Klebanoff M, Carey JC, for the NICHD MFMU Network, Bethesda, MD. Metronidazole did not prevent preterm birth in asymptomatic women with bacterial vaginosis (abstract). Am J Obstet Gynecol 1999;180:S2.
48.Hauth JC, for the NICHD MFMU Network, Bethesda, MD. Response of the three components of a vaginal gram stain score to metronidazole treatment and in relation to preterm birth (abstract). Am J Obstet Gynecol 2000;182:S56.
49.Carey J, Klebanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest JM, Heine RP, Nugent RP, Fischer ML, Leveno KJ, Wapner R, Varner M, and the National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med 2000;342:534–40.
50.Carey JC, Klebanoff M, for the NICHD MFMU Network, Bethesda MD. Metronidazole treatment increased the risk of preterm birth in asymptomatic women with trichomonas (abstract). Am J Obstet Gynecol 2000;182:Ss13.
51.Klebanoff MA, Carey JC, Hauth JC, Hillier SL, Nugent RP, Thom EA, Ernest JM, Heine RP, Wapner RJ, Trout W, Moawad A, Leveno KJ, and the National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl J Med 2001;345:487–93.
52.Erickson SH, Oppenheim GL, Smith GH. Metronidazole in breast milk. Obstet Gynecol 1981;57:48–50.
53.Heisterberg L, Branebjerg PE. Blood and milk concentrations of metronidazole in mothers and infants. J Perinat Med 1983;11:114–20.
54.Moore B, Collier J. Drugs and breast-feeding. Br Med J 1979;2:211.
55.Clements CJ. Metronidazole and breast feeding. NZ Med J 1980;92:329.
56.Passmore CM, McElnay JC, Rainey EA, D’Arcy PF. Metronidazole excretion in human milk and its effect on the suckling neonate. Br J Clin Pharmacol 1988;26:45–51.
57.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.