Recent advances and future directions for uterine diseases diagnosis, pathogenesis, and management in dairy cows
Ahmadi MR, Makki M, Mirzaei A, Gheisari HR. Effects of hypertonic dextrose and paraffin solution as non-antibiotic treatments of clinical endometritis on reproductive performance of high producing dairy cows. Reprod Domest Anim. 2019;54(5):762-71.
Ametaj BN, Iqbal S, Selami F, Odhiambo JF, Wang Y, Ganzle MG, Dunn SM, Zebeli Q. Intravaginal administration of lactic acid bacteria modulated the incidence of purulent vaginal discharges, plasma haptoglobin concentrations, and milk production in dairy cows. Res Vet Sci. 2014;96(2):365-70.
ATLAS Collaboration. Identification and rejection of pile-up jets at high pseudorapidity with the ATLAS detector. Eur Phys J C Part Fields. 2017;77(9):580. PMid:32011613.
Baldrick P. The safety of chitosan as a pharmaceutical excipient. Regul Toxicol Pharmacol. 2010;56(3):290-9.
Barragan AA, Lakritz J, Carman MK, Bas S, Hovingh E, Schuenemann GM. Short communication: assessment of biomarkers of inflammation in the vaginal discharge of postpartum dairy cows diagnosed with clinical metritis. J Dairy Sci. 2019;102(8):7469-75.
Barragan AA, Pineiro JM, Schuenemann GM, Rajala-Schultz PJ, Sanders DE, Lakritz J, Bas S. Assessment of daily activity patterns and biomarkers of pain, inflammation, and stress in lactating dairy cows diagnosed with clinical metritis. J Dairy Sci. 2018;101(9):8248-58.
Baser KH. Biological and pharmacological activities of carvacrol and carvacrol bearing essential oils. Curr Pharm Des. 2008;14(29):3106-19.
Benner M, Ferwerda G, Joosten I, van der Molen RG. How uterine microbiota might be responsible for a receptive, fertile endometrium. Hum Reprod Update. 2018;24(4):393-415.
Bicalho ML, Lima FS, Machado VS, Meira EB Jr, Ganda EK, Foditsch C, Bicalho RC, Gilbert RO. Associations among Trueperella pyogenes, endometritis diagnosis, and pregnancy outcomes in dairy cows. Theriogenology. 2016;85(2):267-74.
Bicalho ML, Machado VS, Oikonomou G, Gilbert RO, Bicalho RC. Association between virulence factors of Escherichia coli, Fusobacterium necrophorum, and Arcanobacterium pyogenes and uterine diseases of dairy cows. Vet Microbiol. 2012;157(1-2):125-31.
Bicalho MLS, Lima S, Higgins CH, Machado VS, Lima FS, Bicalho RC. Genetic and functional analysis of the bovine uterine microbiota. Part II: purulent vaginal discharge versus healthy cows. J Dairy Sci. 2017a;100(5):3863-74.
Bicalho MLS, Machado VS, Higgins CH, Lima FS, Bicalho RC. Genetic and functional analysis of the bovine uterine microbiota. Part I: metritis versus healthy cows. J Dairy Sci. 2017b;100(5):3850-62.
Bicalho RC, Santos TM, Gilbert RO, Caixeta LS, Teixeira LM, Bicalho ML, Machado VS. Susceptibility of Escherichia coli isolated from uteri of postpartum dairy cows to antibiotic and environmental bacteriophages. Part I: isolation and lytic activity estimation of bacteriophages. J Dairy Sci. 2010;93(1):93-104.
Bogado Pascottini O, Probo M, LeBlanc SJ, Opsomer G, Hostens M. Assessment of associations between transition diseases and reproductive performance of dairy cows using survival analysis and decision tree algorithms. Prev Vet Med. 2020;176:104908.
Brick TA, Schuenemann GM, Bas S, Daniels JB, Pinto CR, Rings DM, Rajala-Schultz PJ. Effect of intrauterine dextrose or antibiotic therapy on reproductive performance of lactating dairy cows diagnosed with clinical endometritis. J Dairy Sci. 2012;95(4):1894-905.
Bromfield JJ, Santos JE, Block J, Williams RS, Sheldon IM. Physiology and endocrinology symposium: uterine infection: linking infection and innate immunity with infertility in the high-producing dairy cow. J Anim Sci. 2015;93(5):2021-33.
Bromfield JJ, Sheldon IM. Lipopolysaccharide initiates inflammation in bovine granulosa cells via the TLR4 pathway and perturbs oocyte meiotic progression in vitro. Endocrinology. 2011;152(12):5029-40.
Canning P, Hassfurther R, TerHune T, Rogers K, Abbott S, Kolb D. Efficacy and clinical safety of pegbovigrastim for preventing naturally occurring clinical mastitis in periparturient primiparous and multiparous cows on US commercial dairies. J Dairy Sci. 2017;100(8):6504-15.
Carvalho MR, Penagaricano F, Santos JEP, DeVries TJ, McBride BW, Ribeiro ES. Long-term effects of postpartum clinical disease on milk production, reproduction, and culling of dairy cows. J Dairy Sci. 2019;102(12):11701-17.
Cunha F, Jeon SJ, Daetz R, Vieira-Neto A, Laporta J, Jeong KC, Barbet AF, Risco CA, Galvão KN. Quantifying known and emerging uterine pathogens, and evaluating their association with metritis and fever in dairy cows. Theriogenology. 2018;114:25-33.
Daetz R, Cunha F, Bittar JH, Risco CA, Magalhães F, Maeda Y, Santos JEP, Jeong KC, Cooke RF, Galvão KN. Clinical response after chitosan microparticle administration and preliminary assessment of efficacy in preventing metritis in lactating dairy cows. J Dairy Sci. 2016;99(11):8946-55.
Deng Q, Odhiambo JF, Farooq U, Lam T, Dunn SM, Ametaj BN. Intravaginal lactic Acid bacteria modulated local and systemic immune responses and lowered the incidence of uterine infections in periparturient dairy cows. PLoS One. 2015;10(4):e0124167.
Dervishi E, Zhang G, Hailemariam D, Mandal R, Wishart DS, Ametaj BN. Urine metabolic fingerprinting can be used to predict the risk of metritis and highlight the pathobiology of the disease in dairy cows. Metabolomics. 2018;14(6):83.
Dubuc J, Duffield TF, Leslie KE, Walton JS, LeBlanc SJ. Definitions and diagnosis of postpartum endometritis in dairy cows. J Dairy Sci. 2010;93(11):5225-33.
Escandón BM, Espinoza JS, Perea FP, Quito F, Ochoa R, Lopez GE, Galarza DA, Garzón JP. Intrauterine therapy with ozone reduces subclinical endometritis and improves reproductive performance in postpartum dairy cows managed in pasture-based systems. Trop Anim Health Prod. 2020.
Espadamala A, Pereira R, Pallares P, Lago A, Silva-Del-Rio N. Metritis diagnosis and treatment practices in 45 dairy farms in California. J Dairy Sci. 2018;101(10):9608-16.
Freick M, Kunze A, Passarge O, Weber J, Geidel S. Metritis vaccination in Holstein dairy heifers using a herd-specific multivalent vaccine - Effects on uterine health and fertility in first lactation. Anim Reprod Sci. 2017;184:160-71.
Friedman M. Chemistry and multibeneficial bioactivities of carvacrol (4-isopropyl-2-methylphenol), a component of essential oils produced by aromatic plants and spices. J Agric Food Chem. 2014;62(31):7652-70.
Galvão KN, Bicalho RC, Jeon SJ. Symposium review: the uterine microbiome associated with the development of uterine disease in dairy cows. J Dairy Sci. 2019a;102(12):11786-97.
Galvão KN, Higgins CH, Zinicola M, Jeon SJ, Korzec H, Bicalho RC. Effect of pegbovigrastim administration on the microbiome found in the vagina of cows postpartum. J Dairy Sci. 2019b;102(4):3439-51.
Genís S, Cerri RLA, Bach A, Silper BF, Baylao M, Denis-Robichaud J, Arís A. Pre-calving intravaginal administration of lactic acid bacteria reduces metritis prevalence and regulates blood neutrophil gene expression after calving in dairy cattle. Front Vet Sci. 2018;5:135.
Haimerl P, Heuwieser W, Arlt S. Short communication: meta-analysis on therapy of bovine endometritis with prostaglandin F2alpha-An update. J Dairy Sci. 2018;101(11):10557-64.
Hillmann B, Al-Ghalith GA, Shields-Cutler RR, Zhu Q, Gohl DM, Beckman KB, Knight R, Knights D. Evaluating the information content of shallow shotgun metagenomics. mSystems. 2018;3(6):e00069-18.
Horlock AD, Piersanti RL, Ramirez-Hernandez R, Yu F, Ma Z, Jeong KC, Clift MJD, Block J, Santos JEP, Bromfield JJ, Sheldon IM. Uterine infection alters the transcriptome of the bovine reproductive tract three months later. Reproduction. 2020;160(1):93-107.
Jeon SJ, Cunha F, Ma X, Martinez N, Vieira-Neto A, Daetz R, Bicalho RC, Lima S, Santos JE, Jeong KC, Galvão KN. Uterine microbiota and immune parameters associated with fever in dairy cows with metritis. PLoS One. 2016;11(11):e0165740.
Jeon SJ, Cunha F, Vieira-Neto A, Bicalho RC, Lima S, Bicalho ML, Galvão KN. Blood as a route of transmission of uterine pathogens from the gut to the uterus in cows. Microbiome. 2017;5(1):109.
Jeon SJ, Lima FS, Vieira-Neto A, Machado VS, Lima SF, Bicalho RC, Santos JEP, Galvão KN. Shift of uterine microbiota associated with antibiotic treatment and cure of metritis in dairy cows. Vet Microbiol. 2018;214:132-9.
Jeon SJ, Oh M, Yeo WS, Galvão KN, Jeong KC. Underlying mechanism of antimicrobial activity of chitosan microparticles and implications for the treatment of infectious diseases. PLoS One. 2014;9(3):e92723.
Jeon SJ, Vieira-Neto A, Gobikrushanth M, Daetz R, Mingoti RD, Parize AC, de Freitas SL, da Costa AN, Bicalho RC, Lima S, Jeong KC, Galvão KN. Uterine microbiota progression from calving until establishment of metritis in dairy cows. Appl Environ Microbiol. 2015;81(18):6324-32.
Jiang K, Yang J, Yang C, Zhang T, Shaukat A, Yang X, Dai A, Wu H, Deng G. miR-148a suppresses inflammation in lipopolysaccharide-induced endometritis. J Cell Mol Med. 2020;24(1):405-17.
Kimura K, Goff JP, Kehrli ME Jr, Reinhardt TA. Decreased neutrophil function as a cause of retained placenta in dairy cattle. J Dairy Sci. 2002;85(3):544-50.
Knudsen LR, Karstrup CC, Pedersen HG, Angen O, Agerholm JS, Rasmussen EL, Jensen TK, Klitgaard K. An investigation of the microbiota in uterine flush samples and endometrial biopsies from dairy cows during the first 7 weeks postpartum. Theriogenology. 2016;86(2):642-50.
LeBlanc SJ. Interactions of metabolism, inflammation, and reproductive tract health in the postpartum period in dairy cattle. Reprod Domest Anim. 2012;47(Suppl 5):18-30.
LeBlanc SJ. Review: relationships between metabolism and neutrophil function in dairy cows in the peripartum period. Animal. 2020;14(S1):s44-54.
Lima FS, Bisinotto RS, Ribeiro ES, Greco LF, Ayres H, Favoreto MG, Carvalho MR, Galvão KN, Santos JE. Effects of 1 or 2 treatments with prostaglandin F(2)alpha on subclinical endometritis and fertility in lactating dairy cows inseminated by timed artificial insemination. J Dairy Sci. 2013;96(10):6480-8.
Lima FS, Vieira-Neto A, Snodgrass JA, De Vries A, Santos JEP. Economic comparison of systemic antimicrobial therapies for metritis in dairy cows. J Dairy Sci. 2019;102(8):7345-58.
Lima FS, Vieira-Neto A, Vasconcellos GS, Mingoti RD, Karakaya E, Sole E, Bisinotto RS, Martinez N, Risco CA, Galvão KN, Santos JE. Efficacy of ampicillin trihydrate or ceftiofur hydrochloride for treatment of metritis and subsequent fertility in dairy cows. J Dairy Sci. 2014;97(9):5401-14.
Lopes F, Rosa G, Pinedo P, Santos JEP, Chebel RC, Galvão KN, Schuenemann GM, Bicalho RC, Gilbert RO, Rodrigez-Zas S, Seabury CM, Thatcher W. Genome-enable prediction for health traits using high-density SNP panel in US Holstein cattle. Anim Genet. 2020;51(2):192-9.
Machado VS, Bicalho ML, Meira EB Jr, Rossi R, Ribeiro BL, Lima S, Santos T, Kussler A, Foditsch C, Ganda EK, Oikonomou G, Cheong SH, Gilbert RO, Bicalho RC. Subcutaneous immunization with inactivated bacterial components and purified protein of Escherichia coli, Fusobacterium necrophorum and Trueperella pyogenes prevents puerperal metritis in Holstein dairy cows. PLoS One. 2014;9(3):e91734.
Machado VS, Bicalho ML, Pereira RV, Caixeta LS, Bittar JH, Oikonomou G, Gilbert RO, Bicalho RC. The effect of intrauterine administration of mannose or bacteriophage on uterine health and fertility of dairy cows with special focus on Escherichia coli and Arcanobacterium pyogenes. J Dairy Sci. 2012;95(6):3100-9.
Machado VS, Celestino ML, Oliveira EB, Lima FS, Ballou MA, Galvão KN. The association of cow related factors assessed at metritis diagnosis with metritis cure risk, fertility, milk yield, and culling for untreated and ceftiofur-treated dairy cows. J Dairy Sci. 2020.
Machado VS, Oikonomou G, Ganda EK, Stephens L, Milhomem M, Freitas GL, Zinicola M, Pearson J, Wieland M, Guard C, Gilbert RO, Bicalho RC. The effect of intrauterine infusion of dextrose on clinical endometritis cure rate and reproductive performance of dairy cows. J Dairy Sci. 2015;98(6):3849-58.
Machado VS, Silva TH. Adaptive immunity in the postpartum uterus: potential use of vaccines to control metritis. Theriogenology. 2020;150:201-9.
Maquivar MG, Barragan AA, Velez JS, Bothe H, Schuenemann GM. Effect of intrauterine dextrose on reproductive performance of lactating dairy cows diagnosed with purulent vaginal discharge under certified organic management. J Dairy Sci. 2015;98(6):3876-86.
McNeel AK, Reiter BC, Weigel D, Osterstock J, Di Croce FA. Validation of genomic predictions for wellness traits in US Holstein cows. J Dairy Sci. 2017;100(11):9115-24.
Mitchell GB, Albright BN, Caswell JL. Effect of interleukin-8 and granulocyte colony-stimulating factor on priming and activation of bovine neutrophils. Infect Immun. 2003;71(4):1643-9.
Meira Jr. EBS, Ellington-Lawrence RD, Silva JCC, Higgins CH, Linwood R, Rodrigues MX, et al. Recombinant protein subunit vaccine reduces puerperal metritis incidence and modulates the genital tract microbiome. J Dairy Sci. 2020;103(8):103. PMid:32505392.
Moore SG, Ericsson AC, Behura SK, Lamberson WR, Evans TJ, McCabe MS, Poock SE, Lucy MC. Concurrent and long-term associations between the endometrial microbiota and endometrial transcriptome in postpartum dairy cows. BMC Genomics. 2019;20(1):405.
Nagata S. Gene structure and function of granulocyte colony-stimulating factor. BioEssays. 1989;10(4):113-7.
Oliveira EB, Cunha F, Daetz R, Figueiredo CC, Chebel RC, Santos JE, Risco CA, Jeong KC, Machado VS, Galvão KN. Using chitosan microparticles to treat metritis in lactating dairy cows. J Dairy Sci. 2020;103(8):103.
Peter AT, Bosu WT, DeDecker RJ. Suppression of preovulatory luteinizing hormone surges in heifers after intrauterine infusions of Escherichia coli endotoxin. Am J Vet Res. 1989;50(3):368-73. PMid:2648904.
Piersanti RL, Horlock AD, Block J, Santos JEP, Sheldon IM, Bromfield JJ. Persistent effects on bovine granulosa cell transcriptome after resolution of uterine disease. Reproduction. 2019;158(1):35-46.
Pinedo PJ, Velez JS, Bothe H, Merchan D, Pineiro JM, Risco CA. Effect of intrauterine infusion of an organic-certified product on uterine health, survival, and fertility of dairy cows with toxic puerperal metritis. J Dairy Sci. 2015;98(5):3120-32.
Pomeroy B, Sipka A, Hussen J, Eger M, Schukken Y, Schuberth HJ. Counts of bovine monocyte subsets prior to calving are predictive for postpartum occurrence of mastitis and metritis. Vet Res (Faisalabad). 2017;48(1):13.
Quintero Rodríguez LE, Rearte R, Dominguez G, Luzbel de la Sota R, Madoz LV, Giuliodori MJ. Late embryonic losses in supplemented grazing lactating dairy cows: risk factors and reproductive performance. J Dairy Sci. 2019;102(10):9481-7.
Ribeiro ES, Gomes G, Greco LF, Cerri RLA, Vieira-Neto A, Monteiro PLJ Jr, Lima FS, Bisinotto RS, Thatcher WW, Santos JEP. Carryover effect of postpartum inflammatory diseases on developmental biology and fertility in lactating dairy cows. J Dairy Sci. 2016;99(3):2201-20.
Ribeiro ES. Symposium review: Lipids as regulators of conceptus development: Implications for metabolic regulation of reproduction in dairy cattle. J Dairy Sci. 2018;101(4):3630-41.
Ruiz R, Tedeschi LO, Sepulveda A. Investigation of the effect of pegbovigrastim on some periparturient immune disorders and performance in Mexican dairy herds. J Dairy Sci. 2017;100(4):3305-17.
Sagai M, Bocci V. Mechanisms of action involved in ozone therapy: is healing induced via a mild oxidative stress? Med Gas Res. 2011;1(1):29.
Salilew-Wondim D, Ibrahim S, Gebremedhn S, Tesfaye D, Heppelmann M, Bollwein H, Pfarrer C, Tholen E, Neuhoff C, Schellander K, Hoelker M. Clinical and subclinical endometritis induced alterations in bovine endometrial transcriptome and miRNome profile. BMC Genomics. 2016;17(1):218.
Santos TM, Gilbert RO, Bicalho RC. Metagenomic analysis of the uterine bacterial microbiota in healthy and metritic postpartum dairy cows. J Dairy Sci. 2011;94(1):291-302.
Santos VG, Carvalho PD, Maia C, Carneiro B, Valenza A, Crump PM, Fricke PM. Adding a second prostaglandin F2alpha treatment to but not reducing the duration of a PRID-Synch protocol increases fertility after resynchronization of ovulation in lactating Holstein cows. J Dairy Sci. 2016;99(5):3869-79.
Sheldon IM, Cronin JG, Bromfield JJ. Tolerance and Innate Immunity Shape the Development of Postpartum Uterine Disease and the Impact of Endometritis in Dairy Cattle. Annu Rev Anim Biosci. 2019;7(1):361-84.
Sheldon IM, Cronin JG, Pospiech M, Turner ML. Symposium review: mechanisms linking metabolic stress with innate immunity in the endometrium. J Dairy Sci. 2018;101(4):3655-64.
Sheldon IM, Dobson H. Postpartum uterine health in cattle. Anim Reprod Sci. 2004;82-83:295-306.
Sheldon IM, Lewis GS, LeBlanc S, Gilbert RO. Defining postpartum uterine disease in cattle. Theriogenology. 2006;65(8):1516-30.
Sheldon IM, Rycroft AN, Dogan B, Craven M, Bromfield JJ, Chandler A, Roberts MH, Price SB, Gilbert RO, Simpson KW. Specific strains of Escherichia coli are pathogenic for the endometrium of cattle and cause pelvic inflammatory disease in cattle and mice. PLoS One. 2010;5(2):e9192.
Sheldon IM. Metabolic stress and endometritis in dairy cattle. Vet Rec. 2018;183(4):124-5.
Sicsic R, Goshen T, Dutta R, Kedem-Vaanunu N, Kaplan-Shabtai V, Pasternak Z, Gottlieb Y, Shpigel NY, Raz T. Microbial communities and inflammatory response in the endometrium differ between normal and metritic dairy cows at 5-10 days post-partum. Vet Res (Faisalabad). 2018;49(1):77.
Stangaferro ML, Wijma R, Caixeta LS, Al-Abri MA, Giordano JO. Use of rumination and activity monitoring for the identification of dairy cows with health disorders: part III. Metritis. J Dairy Sci. 2016;99(9):7422-33.
Suntres ZE, Coccimiglio J, Alipour M. The bioactivity and toxicological actions of carvacrol. Crit Rev Food Sci Nutr. 2015;55(3):304-18.
Tadepalli S, Narayanan SK, Stewart GC, Chengappa MM, Nagaraja TG. Fusobacterium necrophorum: a ruminal bacterium that invades liver to cause abscesses in cattle. Anaerobe. 2009;15(1-2):36-43.
Tchesnokova V, Aprikian P, Kisiela D, Gowey S, Korotkova N, Thomas W, Sokurenko E. Type 1 fimbrial adhesin FimH elicits an immune response that enhances cell adhesion of Escherichia coli. Infect Immun. 2011;79(10):3895-904.
Wathes DC. Mechanisms linking metabolic status and disease with reproductive outcome in the dairy cow. Reprod Domest Anim. 2012;47(Suppl 4):304-12.
Wisnieski L, Norby B, Pierce SJ, Becker T, Gandy JC, Sordillo LM. Cohort-level disease prediction using aggregate biomarker data measured at dry-off in transition dairy cattle: A proof-of-concept study. Prev Vet Med. 2019;169:104701.
World Health Organization – WHO. WHO guidelines on use of medically important antimicrobials in food-producing animals [Internet]. Genebra: WHO; 2017 [cited 2020 May 30]. Available from:
Zhang G, Deng Q, Mandal R, Wishart DS, Ametaj BN. DI/LC-MS/MS-based metabolic profiling for identification of early predictive serum biomarkers of metritis in transition dairy cows. J Agric Food Chem. 2017;65(38):8510-21.
Zinicola M, Batista CP, Bringhenti L, Meira EBS Jr, Lima FS, McDonough SP, Bicalho RC. Effects of recombinant bovine interleukin-8 (rbIL-8) treatment on health, metabolism, and lactation performance in Holstein cattle IV: insulin resistance, dry matter intake, and blood parameters. J Dairy Sci. 2019b;102(11):10340-59.
Zinicola M, Bicalho MLS, Santin T, Marques EC, Bisinotto RS, Bicalho RC. Effects of recombinant bovine interleukin-8 (rbIL-8) treatment on health, metabolism, and lactation performance in Holstein cattle II: postpartum uterine health, ketosis, and milk production. J Dairy Sci. 2019a;102(11):10316-28.
Zinicola M, Korzec H, Teixeira AGV, Ganda EK, Bringhenti L, Tomazi A, Gilbert RO, Bicalho RC. Effects of pegbovigrastim administration on periparturient diseases, milk production, and reproductive performance of Holstein cows. J Dairy Sci. 2018;101(12):11199-217.
Zinicola M, Menta PR, Ribeiro BL, Boisclair Y, Bicalho RC. Effects of recombinant bovine interleukin-8 (rbIL-8) treatment on health, metabolism, and lactation performance in Holstein cattle III: administration of rbIL-8 induces insulin resistance in bull calves. J Dairy Sci. 2019;102(11):10329-39.