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: 854-855

Henrik Toft Sørensena,b,e,*, Helle Larsenc, Elise Snitker Jensend, Ane Marie Thulstrupa,e, Henrik C. Schønheyderd, Gunnar Lauge Nielsenb, Andrew Czeizelf and the EUROMAP Study Group,{dagger}

aThe Danish Epidemiology Science Centre at the Department of Epidemiology and Social Medicine, University of Aarhus, Vennelyst Boulevard 6, DK-8000 Aarhus C, Denmark bThe Department of Medicine M, Aalborg Hospital, DK-9000 Aalborg, Denmark cThe Department of Gynaecology and Obstetrics, Aalborg Hospital, 9000 Aalborg, Denmark dThe Department of Clinical Microbiology, Aalborg Hospital, DK-9000 Aalborg, Denmark eThe Department of Medicine V, Aarhus University Hospital, DK-8000 Aarhus C, Denmark fFoundation for the Community Control of Hereditary Diseases, Budapest, Hungary

Sir,

Metronidazole is widely used in the treatment of trichomoniasis and bacterial vaginosis in women.1 The agent crosses the placenta throughout gestation. Available data on the safety of the drug during pregnancy are contradictory and valid data on the safety of metronidazole in pregnancy are still needed.2,3 A population-based cohort study in North Jutland County, Denmark was conducted to compare the prevalence of congenital abnormalities, low birth weight and preterm delivery among fetuses exposed to metronidazole (for details regarding methodology see Sørensen et al., 19994). All pregnant women (c. 35,000) who gave birth in the county from 1991 to 1996 were identified from the Danish Medical Birth Registry. The Danish National Health Service offers a 50% reimbursement of expenditure on metronidazole which is purchased on prescription only. Since 1 January 1991 all prescription data have been stored in the Pharmaco-Epidemiological Prescription Database of North Jutland.5 This database was used to identify both exposed women (redeeming prescriptions for metronidazole) and controls (women not exposed to any kind of reimbursed medicine during pregnancy). Pregnancy outcome data were collected from the Danish Medical Birth Registry; and the Danish Hospital Discharge Registry was used to identify congenital abnormalities which accordingly were all diagnosed after birth. By means of the unique Personal Registration Number unambiguous linkages between the various registries could be performed. The gestational age at time of take-up of prescription was calculated based on the reported gestational age at delivery. Two time windows were defined: (i) interval 1, 30 days before conception to the end of the first trimester; (ii) interval 2, second and third trimester.

All prescriptions for metronidazole during pregnancy were classified according to these two time windows. We used logistic regression models to analyse the risk of congenital abnormalities, low birth weight (<2500 g) and preterm birth (<37 weeks) adjusted for maternal age, birth order, gestational age and smoking habit. We used data from interval one to examine the risk of congenital abnormalities and from intervals one and two to examine the risk of preterm delivery. Owing to few newborns with low birth weight, it was not possible to perform logistic regression analysis.

From the Prescription Database we identified a total of 138 prescriptions for metronidazole (ATC code P01A B01) obtained at the pharmacies by 124 women from 1991 to 1996. In one case prescriptions were issued in both time intervals. The control group consisted of 13,327 pregnancies. Apart from a significantly higher proportion of smokers (P < 0.001) there were no differences between exposed and control groups at baseline. The prevalence proportion of congenital abnormalities was 2.4% in exposed and 5.2% in controls. The Table shows the results of logistic regression analysis. No elevated risk of congenital abnormalities was found, odds ratio 0.44 (95% CI 0.11–1.81). The two congenital abnormalities among those exposed in time interval one were transpositio vasorum with ventricular septum defect and hyperteleorism. There were four preterm deliveries among 84 (4.8%) women exposed in the first trimester; six among 124 (4.8%) women exposed at any time during pregnancy versus 793 in the control group of 13,327 (6.0%) pregnancies, giving an adjusted odds ratio of 0.80 (95% CI 0.35–1.83). There was no difference in mean birth weight after adjustment for maternal age, birth order, gestational age and smoking habit.


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Table. Logistic regression analyses of pregnancy outcome in women exposed to metronidazole compared with the reference group odds ratios with 95% confidence intervals
 
It is important to note the advantages and limitations of our study. We have a complete registration of prescriptions and births which reduces the risk of selection bias. We had information about gestational age, allowing us to determine the time of exposure in pregnancy. The outcome data have proved to be of high validity and are obtained independently of exposure information.6 The weaknesses of the study are both a matter of low statistical power owing to a limited number of exposed subjects and also our inability to control for other potentially confounding factors. The study design did not permit identification of malformed fetuses, detected at prenatal diagnosis, and aborted fetuses.

Our study did not reveal any elevated risk of congenital abnormalities, preterm delivery or low birth weight among women exposed to metronidazole. The non-teratogenicity of metronidazole is difficult to prove, but the existing available data indicate no major risks and no indication for the termination of pregnancies.

Acknowledgments

The authors wish to thank the staff at the Department of Health Insurance and Preventive Medicine and Hospital Discharge Registries in the County of North Jutland (Sygesikringen, Amtsgaarden) for their excellent assistance in preparing the data for analyses. The study was approved by the local ethics committee (no. 2-16-4-5-95(95/104)). This study was supported by grants from the EU BIOMED programme (contract No. BMH4-CT97-2430), the Danish Medical Research Council (grant no. 9700677), the North Jutland Research Council, Aarhus University Foundation and Helsefonden (grant no. 11/121-95). The activities of the Danish Epidemiology Science Centre are financed by a grant from the Danish National Research Foundation.

Notes

* Corresponding author. Tel: +45-89-42-60-76; Fax: +45-89-42-61-10; E-mail: hts{at}soci.au.dk Back

{dagger} Project management group. Henrik Toft Sørensen, Jørn Olsen, Andrew Czeizel, Gunnar Lauge Nielsen, Lolkje De Jong-van den Berg, Lorentz Irgens, Ulf Bergman. Other members of the study group: Charlotte Olesen, Flemming Hald Steffensen, Lars Pedersen, Rolv T. Lie & Corinne de Vries. Back

References

1 . Ralph, S. G., Rutherford, A. J. & Wilson, J. D. (1999). Influence of bacterial vaginosis on conception and miscarriage in the first trimester: cohort study. British Medical Journal 319, 220–3.[Abstract/Free Full Text]

2 . Briggs, G. G., Freeman, R. K. & Yaff, S.J. (1998) Drugs in Pregnancy and Lactation. 5th edn, Williams & Wilkins, Baltimore, USA.

3 . Burtin, P., Taddio, A., Ariburnu, O., Einarson, T. R. & Koren, G. (1995). Safety of metronidazole in pregnancy: A meta-analysis. American Journal of Obstetrics and Gynecology 172, 525–9.[ISI][Medline]

4 . Sørensen, H. T., Nielsen, G. L., Olesen, C., Larsen, H., Steffensen, F. H., Schønheyder, H. C. et al. (1999). Risk of malformations and other outcomes in children exposed to fluconazole in utero. British Journal of Clinical Pharmacology 48, 234–8.[ISI][Medline]

5 . Nielsen, G. L., Sørensen, H. T., Weijin, Z., Steffensen, F. H. & Olsen, J. (1997). The Pharmaco-Epidemiologic Prescription Database of North Jutland. International Journal of Risk Safety in Medicine 10, 203–5.

6 . Kristensen, J., Langhoff-Ross, J., Skovgaard, L. T. & Kristensen, F. B. (1996). Validation of the Danish Birth Registration. Journal of Clinical Epidemiology 49, 893–7.[ISI][Medline]





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