Metronidazole

Name: METRONIDAZOLE
Class: Anti-infective/Amebicide/ Trichomonacide
Risk Factor: BM

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 (1,2 and 3). The pharmacokinetics of metronidazole in pregnant women have been reported (4,5).
Reproduction studies have been 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) have revealed no fetal harm (6). After intraperitoneal administration in mice, however, some fetal deaths were noted (6).
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 to 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) (11). 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 (95% 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 for 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 under 5 years of age prevented the identification of potential effects on later developing cancers such as Hodgkin disease, Ewing sarcomas, and osteosarcoma (12).
Several studies, individual case reports, and reviews have described the safe use of metronidazole during pregnancy (13,14,15,16,17,18,19,20,21,22,23,24,25,26 and 27). Included among these is a 1972 review summarizing 20 years of experience with the drug and involving 1,469 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, have found an increased risk when the agent was used early in pregnancy (9,28,29 and 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 five congenital anomalies: hydrocele (two), congenital dislocated hip (female twin), metatarsus varus, and mental retardation (both parents mentally retarded). 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 which had 1st trimester exposure to metronidazole (28). A possible association with malformations was found (RR 2.02) based on defects in four children. The statistical significance of this finding is unknown. Independent confirmation is required to determine the actual risk.
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.
In another case report, 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 described is unknown.
As of May 1987, the FDA had received reports of 27 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 1980–1983, cited 1,020 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) (31). 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 4,264 spontaneous abortions compared to 1,020 exposures among 55,736 deliveries.
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, 2,445 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 1,322 exposed (1,318 livebirths; 4 stillbirths) and 1,328 nonexposed (1,320 livebirths; 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 to 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, 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 increase 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 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, 1,041 (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 ± 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).
A population-based cohort study on the use of metronidazole during pregnancy from 1991 to 1996 was conducted in Denmark and reported in 1999 (36). 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 transpositio 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 (36). 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 (36).
Metronidazole has been shown to markedly potentiate the fetotoxicity and teratogenicity of alcohol in mice (37). Human studies of this possibly clinically significant interaction have not been reported.
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 (38,39,40,41,42,43,44,45,46,47 and 48). 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 (38).
A prospective, randomized, double-blind, placebo-controlled study first published in abstract form in 1993 (39) and then in full in 1994 (40) 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) (40).
Another prospective randomized, double-blind, placebo-controlled study first published in abstract form in 1993 (41) and then in full in 1995 (42) 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) (42). 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 to 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 were administered. Eight women were lost to follow-up. A total of 110 women (26%) in the active group delivered preterm (<37 weeks) compared to 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 to 49% in those receiving placebo (p=0.006). The positive association with antiinfective 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) (42).
A 1997 randomized, placebo-controlled 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 (43). 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 (44). The subjects in both groups had threatened idiopathic preterm labor and intact membranes. The antiinfective 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 to 34 weeks' gestation from six clinics in the Copenhagen area. Treatment with the antiinfectives was associated with prolongation of gestation (47.5 days vs. 27 days, p<0.05), higher gestational age at birth (37 weeks 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) (44). 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. 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 (45,46 and 47), or increased the risk for that outcome (48).
In summary, although some of the available reports have arrived at conflicting conclusions as to the safety of metronidazole in pregnancy, the majority of the published evidence now appears to suggest that the anti-infective does not present a significant risk to the fetus. A possible very small risk for cleft lip with or without palate has been reported, but the validity and the clinical significance of this finding is questionable. It is also not possible to completely assess the risk to the fetus from the potential carcinogenic potential of metronidazole. Although one study found no significant increase for the risk of cancer in children under the age of 5 years, there was a nonsignificant increase for neuroblastoma. Moreover, that study did not address the issue of cancers with an onset at a later age. Obviously, 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 American College of Obstetricians and Gynecologists (ACOG), the manufacturer, and the American Society of Health-System Pharmacists consider metronidazole to be contraindicated during the 1st trimester in patients with trichomoniasis or bacterial vaginosis (6,49,50). ACOG recommends that clindamycin (orally or intravaginally) should be used during the 1st trimester for symptomatic bacterial vaginosis (50). The use of metronidazole for trichomoniasis or vaginosis during the 2nd and 3rd trimesters is acceptable, either as a single 2-g oral dose or a 7-day course of 750 to 1000 mg/day in divided doses (50). For other indications, metronidazole can be used during pregnancy if there are no other alternatives with established safety profiles. In these cases, the patient should be counseled as to the potential risks and her consent obtained prior to initiating therapy.

Breast Feeding Summary

Metronidazole is excreted into breast milk. Following a single 2-g oral dose in three patients, peak milk concentrations in the 50–60 µg/mL range were measured at 2–4 hours (51). With normal breast feeding, 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 (51).
In women treated with divided oral doses of either 600 or 1200 mg/day, the mean milk levels were 5.7 and 14.4 µg/mL, respectively (52). 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 µg/mL with maximum concentrations of 25 µg/mL (53).
One report described diarrhea and secondary lactose intolerance in a breast-fed infant whose mother was receiving metronidazole (54). 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. Because of the potential mutagenic effects and the unknown consequences of exposure in the nursing infant, the American Academy of Pediatrics recommends using metronidazole with caution during lactation (55).
A single, 2-g oral dose has been recommended by the Centers for Disease Control if metronidazole is used for trichomoniasis during lactation (49). If this dose is given, the Academy recommends discontinuing breast feeding for 12–24 hours to allow excretion of the drug (55).

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