Animal Reproduction (AR)
Animal Reproduction (AR)
Original Article

Effect of metronidazole on placental and fetal development in albino rats

Welma Emídio da Silva; Ismaela Maria Ferreira de Melo; Yuri Mateus Lima de Albuquerque; Aline Ferreira da Silva Mariano; Valéria Wanderley-Teixeira; Álvaro Aguiar Coelho Teixeira

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Abstract: Metronidazole is an antiprotozoal and antibacterial used in gynecology and obstetrics for the treatment of parasitic infections. However, despite having clinical use for more than three decades, questions about the safety of its use during pregnancy is not well understood. Thus, the present study evaluated the effect of metronidazole on placental and fetal development in pregnant rats. Metronidazole was orally administered by gavage at a dosage of 130 mg/kg for 7 and 14 days. Morphological analysis, morphometry and immunohistochemistry were performed at the implantation sites and placentas with 14 days of development. The results showed that in the treated group there was a significant reduction in the number of implantation sites, total placental disc area and constituent elements of the labyrinth and spongiotrophoblast layers. Histochemical analysis revealed no significant changes in the content of collagen, elastic and reticular fibers. The TUNEL test showed apoptotic activity in the implantation sites and placentas with 14 days of development independent of the treatment. There was no evidence of malformation in the neonates. However, there was a significant reduction in the number and weight of neonates in the group treated with metronidazole when compared to the control group. Thus, it is concluded that the administration of 130 mg/kg of metronidazole during pregnancy in rats, in addition to interfering with the number of implanted embryos, promotes changes in placental structure and interferes with fetal development. This suggests that this drug should be used with caution during pregnancy.


metronidazole, pregnancy, placental development, reproduction


Achache H, Revel A. Endometrial receptivity markers, the journal to successful embryo implantation. Hum Reprod Update. 2006;12(6):731-46. PMid:16982667.

Agarwal A, Kanekar S, Sabat S, Thamburaj K. Metronidazole-induced cerebellar toxicity. Neurol Int. 2016;8(1):6365. PMid:27127600.

Amadeu TP, Coulomb B, Desmouliere A, Costa AMA. Cutaneous wound healing: myofibroblastic differentiation and in vitro models. Int J Low Extrem Wounds. 2003;2(2):60-8. PMid:15866829.

Bernardi MM, Spinosa HS. Exposição aos medicamentos durante o período perinatal. In: Spinosa HS, Górniak SL, Bernardi MM. Farmacologia aplicada à medicina veterinária. 6. ed. Rio de Janeiro: Guanabara Koogan; 2017. p. 900-8.

Boss PK, Buckeridge EJ, Poole A, Thomas MR. New insights into grapevine flowering. Funct Plant Biol. 2003;30(6):593-606.

Correia-da-Silva G, Bell SC, Pringle JH, Teixeira NA. Patterns of uterine cellular roliferation and apoptosis in the implantation site of the rat during pregnancy. Placenta. 2004;25(6):538-47. PMid:15135237.

El-Nahas AF, El-Ashmawy IM. Reproductive and cytogenetic toxicity of metronidazole in male mice. Basic Clin Pharmacol Toxicol. 2004;94(5):226-31. PMid:15125692.

Girish MB, Patil PA. The influence of some azoles on wound healing in albino rats. Indian J Pharmacol. 2005;37(4):247-50.

Grover JK, Vats V, Srinivas M, Das SN, Jha P, Gupta DK, Mitra DK. Effect of metronidazole on spermatogenesis and FSH, LH and testosterone levels of pre-pubertal rats. Indian J Exp Biol. 2001;39(11):1160-2. PMid:11906111.

Gülmezoglu AM, Azhar M. Interventions for trichomoniasis in pregnancy. Cochrane Database Syst Rev. 2011;11(5):CD000220. PMid:21563127.

Hildebrand KAMD, Gallant-Behm CL, Kydd AS, Hart DA. The basics of soft tissue healing and general factors that influence such healing. Sports Med Arthrosc Rev. 2005;13(3):136-44.

Ho MH, Chang HC, Chang YC, Claudia J, Lin TC, Chang PC. PDGF-metronidazole-encapsulated nanofibrous functional layers on collagen membrane promote alveolar ridge regeneration. Int J Nanomedicine. 2017;12:5525-35. PMid:28831251.

Irvine L, Flynn RWV, Libby G, Crombie IK, Evans JM. Drugs dispensed in primary care during pregnancy: a record-linkage analysis in Tayside, Scotland. Drug Saf. 2010;33(7):593-604. PMid:20553060.

Kazy Z, Puhó E, Czeizel AE. Teratogenic potential of vaginal metronidazole treatment during pregnancy. Eur J Obstet Gynecol Reprod Biol. 2005;123(2):174-8. PMid:16316810.

Meça KKOL, Martins AS, Del Puerto HL, Vasconcelos AC. Apoptose e expressão de Bcl-2 e das caspases 3 e 8 em placenta bovina, em diferentes estágios de gestação. Arq Bras Med Vet Zootec. 2010;62(2):258-64.

Medeiros MA, Riet-Correa F, Dantas FPM, Santos JRS, Medeiros RMT. Efeitos teratogênicos de Prosopis juliflora em ratos e análise da toxicidade das vagens. Pesq Vet Bras. 2014;34(11):1089-93.

Melo IMF, Silva WE, Teixeira AAC, Wanderley-Teixeira V, Barreto SBFP, Lapa Neto CJC, Andrade FM. Efeito da enrofloxacina sobre a interação blastocisto endométrio e seu reflexo no desenvolvimento placentário e fetal em ratas. Arq Bras Med Vet Zootec. 2014;66(5):1406-12.

Mendling W, Palmeira-de-Oliveira A, Biber S, Prasauskas V. An update on the role of Atopobium vaginae in bacterial vaginosis: what to consider when choosing a treatment? A mini review. Arch Gynecol Obstet. 2019;300(1):1-6. PMid:30953190.

Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernández-Díaz S. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet Gynecol. 2011;205(1):51.e1-8. PMid:21514558.

Muanda FT, Sheehy O, Bérard A. Use of antibiotics during pregnancy and risk of spontaneous abortion. CMAJ. 2017;189(17):E625-33. PMid:28461374.

Mudry MD, Martínez-Flores I, Palermo AM, Carballo MA, Egozcue J, García Caldés M. Embryolethality induced by metronidazole (MTZ) in Rattus norvegicus. Teratog Carcinog Mutagen. 2001;21(3):197-205. PMid:11301414.

Mudry MD, Palermo AM, Merani MS, Carballo MA. Metronidazole-induced alterations in murine spermatozoa morphology. Reprod Toxicol. 2007;23(2):246-52. PMid:17184970.

Natale A, Candiani M, Merlo D, Izzo S, Gruft L, Busacca M. Human chorionic gonadotropin level as a predictor of trophoblastic infiltration into the tubal wall in ectopic pregnancy: a blinded study. Fertil Steril. 2003;79(4):981-6. PMid:12749441.

Rao CM, Ghosh A, Raghothama C, Bairy KL. Does metronidazole reduce lipid peroxidation in burn injuries to promote healing? Burns. 2002;28(5):427-9. PMid:12163280.

Rasheed ST, Hasan II, Khalaf MT. Study the effect of Metronidazole Drug (MTZ) and Rhuscoriaria (Sumac) on testicular tissues and sperms of male white mice. Tikrit Journal of Pure Science. 2018;23(1):38-42.

Ribeiro AS, Silva MV, Guerra PG, Saick KW, Uliana MP, Loss R. Risco potencial do uso de medicamentos durante a gravidez e a lactação. Infarm. 2013;25(1):63-8.

Rodrigues HG, Meireles CG, Lima JTS, Toledo GP, Cardoso JL, Gomes SL. Efeito embriotóxico, teratogênico e abortivo de plantas medicinais. Rev Bras Plantas Med. 2011;13(3):359-66.

Sahin L, Nallani SC, Tassinari MS. Medication use in pregnancy and the pregnancy and lactation labeling rule. Clin Pharmacol Ther. 2016;100(1):23-5. PMid:27082701.

Sampaio CPP, Biondo-Simões MLP, Trindade LCT, Farias RE, Pierin RJ, Martins RC. Alterações inflamatórias provocadas pelo metronidazol em feridas: estudo experimental em ratos. J Vasc Bras. 2009;8(3):232-7.

Shennan A, Crawshaw S, Briley A, Hawken J, Seed P, Jones G, Poston L. A randomised controlled Trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study. BJOG. 2006;113(1):65-74. PMid:16398774.

Smith SC, Baker PN, Symonds EM. Placental apoptosis in normal human pregnancy. Am J Obstet Gynecol. 1997;177(1):57-65. PMid:9240583.

Sohrabi D, Alipour M, Awsatmellati A. Effect of metronidazole on spermatogenesis, plasma gonadotrophins and testosterone in male rats. Iran J Pharm Res. 2007;6:279-83.

Souza GN, Vieira TCSB, Campos AAS, Leite APL, Souza E. Tratamento das vulvovaginites na gravidez. Femina. 2012;40:125-8.

Sutherland A. Mechanisms of implantation in the mouse: differentiation and functional importance of trophoblast giant cell behavior. Dev Biol. 2003;258(2):241-51. PMid:12798285.

Thompson K, Newcomb DL, Moffat GJ, Zalikowski J, Chellman GJ, McNerney ME. Evaluation of early fetal exposure to vaginally-administered- metronidazole in pregnant cynomolgus monkeys. Reprod Toxicol. 2016;59:17-21. PMid:26524246.

Trindade LC, Biondo-Simões ML, Sampaio CP, Farias RE, Pierin RJ, Chomiski M No. Avaliação do usotópico do metronidazol no processo de cicatrização de feridas: um estudo experimental. Rev Col Bras Cir. 2010;37(5):358-63. PMid:21181002.

Uribe-Velásquez LF, Souza MIL, Osorio JH. Resposta ovariana de cabras submetidas a implantes de progesterona seguidos de aplicações de gonadotrofina coriônica equina. Rev Bras Zootec. 2010;39(6):1214-22.

Vicente D, Pérez-Trallero E. Tetraciclinas, sulfamidas y metronidazol. Enferm Infecc Microbiol Clin. 2010;28(2):122-30. PMid:20097452.

Wu X, Cheng B, Cai ZD, Lou LM. Determination of the apoptotic index in osteosarcoma tissue and its relationship with patients prognosis. Cancer Cell Int. 2013;13(1):1-4. PMid:23734671.

Zybina TG, Zybina EV, Kiknadze II, Zhelezova AI. Polyploidization in the trophoblast and uterine glandular epithelium of the endotheliochorial placenta of silver fox (Vulpes fulvusDesm.), as revealed by the DNA content. Placenta. 2001;22(5):490-8. PMid:11373160.

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