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Can we use metronidazole during pregnancy and breastfeeding?: Putting an end to the controversy
A. Einarson, RN; E. Ho; G. Koren, MD, FRCPC
Two of my patients have been diagnosed with giardiasis, and I would like to treat them with the drug of choice for this infection, metronidazole (Flagyl®). One of them is 6 weeks pregnant and the other is breastfeeding a 2-month-old infant, and I have received conflicting information about the safety of this drug during pregnancy and breastfeeding. What should I do?
Although metronidazole has been on the market for almost 40 years, its use remains controversial during pregnancy and breastfeeding. Recent evidence has shown, however, that this drug is not associated with adverse effects during either pregnancy or breastfeeding.
Metronidazole is bactericidal against anerobic bacteria. It exerts trichomonacidal activity and is also active against Giardia lamblia and Entamoeba histolytica. Its exact mechanism of action is unknown. A chemically reactive reduced form of metronidazole appears to be responsible for the drugís activity.1
Use of metronidazole during pregnancy has been controversial. The drug is mutagenic in bacteria and carcinogenic in rodents, but has never, in almost 40 years of use, been shown to be associated with human cancer.2,3 These concerns, together with some old case reports describing three cases of midline facial defects, are probably the main reason this drug has not been recommended for use during pregnancy.4
Adding to the fear and uncertainty is a passage in the product monograph describing use of metronidazole during pregnancy: "metronidazole crosses the placental barrier; it should be withheld during the first trimester. In addition, it is advisable that administration be avoided during the second and third trimesters; however, if treatment is considered necessary, its use requires that the potential benefits outweigh the possible risks."1 After reading that, it is quite understandable that physicians would hesitate to prescribe this drug to pregnant women, even when indicated.
The latest studies, which examined the cases of thousands of women exposed to metronidazole during pregnancy, including a Medicaid cohort study, a large case-control study, and two meta-analyses, have concluded that there is no evidence that using metronidazole during pregnancy increases the rate of major birth defects above the baseline rate of 1% to 3% or that there are any detectable adverse effects on fetuses.5-8
Most drugs are excreted into breast milk in small amounts (ie, less than 5% of the motherís dose corrected for the infantís body weight) and are generally considered safe to use because it is thought that full-term infants can handle that amount of drug. Use of metronidazole during breastfeeding has been controversial, however, probably because it is excreted into breast milk in relatively large amounts, up to 20%. Despite this, there have been no reports of adverse effects on breastfed infants of mothers who took metronidazole.9 Furthermore, in a group of 12 mothers who received 400 mg of metronidazole three times daily and breastfed their babies, no adverse reactions were seen in any of the babies.10
- Rhône-Poulenc Rorer. Product monograph (Flagyl®). Ville St-Laurent, Que: Rhône-Poulenc Rorer; 1999.
- Finegold SM. Metronidazole. Ann Intern Med 1980;93:585-7.
- Beard CM, Noller KL, OíFallon WM, Kurland LT, Dockerty MB. Lack of evidence for cancer due to use of metronidazole. N Engl J Med 1979;301:519-22.
- Cantu JM, Garcia-Cruz D. Midline facial defect as a teratogenic effect of metronidazole. Birth Defects 1982;18:85-8.
- Piper JM, Mitchel EF, Ray WA. Prenatal use of metronidazole and birth defects: no association. Obstet Gynecol 1993;82(3):348-52.
- Czeizel AE, Rockenbauer M. A population based case-control teratologic study of oral metronidazole. Br J Obstet Gynaecol 1998;105(3):322-7.
- Burtin P, Taddio A, Ariburnu O, Einarson TR, Koren G. Safety of metronidazole in pregnancy: a meta-analysis. Am J Obstet Gynecol 1995;172(2 Pt 1):525-9.
- Caro-Paton T, Carvajal A, Martin de Diego I, Alvarez Requejo A, Martin Amas LH, Rodriguez Pinilla E, et al. Is metronidazole teratogenic? A meta-analysis. Br J Clin Pharmacol 1997;44(2):179-82.
- Thomas Hale. Medications and motherís milk. Amarillo, Tex: Pharmasoft Medical Publishing; 1998. p. 455.
- Passmore CM, McElnay JC, Rainey EA, DíArcy PF. Metronidazole excretion in human milk and its effect on suckling neonates. Br J Clin Pharmacol 1988;26(1):45-51.