An evaluation of the safety of metronidazole in pregnancy is asked.

Fråga: An evaluation of the safety of metronidazole in pregnancy is asked.

Sammanfattning: A single low-dose treatment course with metronidazole (upto 1000 mg/day) can be considered safe during the latter trimesters of pregnancy. The number of pregnant women treated during the first trimester is relatively low, which makes it more difficult to draw an unequivocal conclusion on the safety of metronidazole treatment during early pregnancy. In such a case, it may be wisest to postpone treatment with metronidazole until the latter trimesters and to use local symptomatic treatment during those first weeks.

Svar: Questions about the safety of metronidazole during pregnancy have been dealt with before adequately (1-5), but some background on the suggested mutagenic, carcinogenic and teratogenic properties of this antimicrobial agent may be useful.

The genotoxic effect of the nitroimidazole derivatives, which is also their therapeutic effect, depends on 5-nitro reduction to an electrophilic metabolite. This transformation does however not occur to a significant extent in normal mammalian cells since they lack the necessary enzymes for this reduction. Although an increased risk of tumour development with metronidazole treatment has been described in mice and rats, this was mainly due to nonspecific effects which are not relevant to the human situation (6). Correspondingly, in 771 women treated with metronidazole no increased cancer incidence was observed after a follow-up period of 10 years or more (7).

Since metronidazole passes freely through the placental barrier, it may have an adverse effect on the foetus. Although most studies describe the safe use of metronidazole during all stages of pregnancy, some investigations found an increased risk when the drug was used early in pregnancy.

Summarizing all studies that were published between 1960 and 1970, a total of 1419 women treated with metronidazole were followed-up until delivery: 205 of these women were treated in the first trimester, 919 in the second or third trimester and in the remaining 295 the time of treatment is not stated (based on reference 8). Therapeutic doses were between 250-1000 mg daily during 7-10 days. The incidences of spontaneous abortion (6 per cent), stillbirth (1.4 per cent) and congenital abnormalities (1.7 per cent) were not higher than in the general population. There was no predominance of any particular type of abnormality which could be related to metronidazole treatment, and in many cases of stillbirth or malformation other circumstances than metronidazole treatment were considered to be the probable cause. The same results were obtained by Morgan (9), who studied 880 patients with trichomoniasis in pregnancy, of whom 597 received treatment with metronidazole (200 mg 3x daily during 7 or 10 days); 62 during the first trimester, 284 during the second, and 251 during the third. She concluded that metronidazole did not affect the incidence of small-for-date or premature babies, and the rate of stillbirth or congenital abnormalities did not differ significantly either from that of the untreated women with trichomonal infections or from that of all patients delivered in her unit.

In the same period, the Collaborative Perinatal Project monitored 50.282 mother-child pairs, 31 of which had first trimester exposure to metronidazole. A possible association with malformations was found (relative risk 2.02) based on defects in four children. The statistical significance of this finding is unknown (cf 10). In a 1979 report, metronidazole was used in 57 pregnancies, including 23 during the first trimester (7). Three of the first 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). Evaluation of these data is very difficult because of the small numbers and possible involvement of genetic factors. Two mothers, treated with metronidazole during the 5th-7th weeks of gestation for amebiasis, gave birth to infants with midline facial defects (11). Diiodohydroxyquinoline was also used in one of the pregnancies. One of the infants had holotelencephaly and one had unilateral cleft lip and palate. A relationship between use of the drug during organogenesis and the observed defects was suggested, but no such defects have been found in any of the other here described studies. 1 Drugline nr 09396 (year )

2 Drugline nr 07229 (year )
3 Drugline nr 06916 (year )
4 Drugline nr 06664 (year )
5 Drugline nr 05686 (year )
6 Roe FJC: Safety of nitroimidazoles. Scand J Infect Dis Suppl 1985; 46: 72-81

7 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: 519-522 8 Berget A, Weber T: Metronidazol and pregnancy. Ugeskr Laeg 1972; 134: 2085-2089 9 Morgan I: Metronidazole treatment in pregnancy. Int J Gynaecol Obstet 1978; 15: 501-502 10 In Briggs GG, Freeman RK, Yaffe SJ (Eds.) Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neonatal Risk, pp. 292/m-294/m, Williams & Wilkins, Baltimore, U. S. A., 2nd ed., 1986 11 Cantu JM, Garcia-Cruz D: Midline facial defect as a teratogenic effect of metronidazole. Birth Defects 1982; 18: 85-88