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Invited review: Effectiveness of precalving treatment on postcalving udder health in nulliparous dairy heifers: A systematic review and meta-analysis

Open ArchivePublished:March 07, 2018DOI:https://doi.org/10.3168/jds.2017-14301

      ABSTRACT

      Clinical mastitis affects 3% of primiparous dairy cattle (heifers) in the first month after calving. Additionally, the prevalence of intramammary infection (IMI) in the months before first calving is high, resulting in a high prevalence of heifers calving with IMI. Precalving therapy is an accepted recommendation for reducing mastitis in multiparous cows, but prophylactic treatment for heifers is uncommon in North America. Objectives of this study were to (1) quantify changes in postcalving udder health in heifers following application of a precalving treatment; (2) compare effectiveness among various types of treatments; and (3) compare effectiveness of various types of treatments against specific pathogens. A systematic review was conducted comparing interventions aimed at improving udder health in heifers. Of 62 included studies, 48 clinical trials were used in a meta-analysis. Data were synthesized using a random effects model for meta-analysis, followed by sub-group analyses comparing treatment types, and specific pathogens with statistical testing using meta-regression. Occurrence of mastitis (defined as elevated somatic cell count, clinical mastitis, and IMI) was reduced in treated heifers compared with untreated controls with a pooled risk ratio of treated to untreated heifers of 0.56 (95% confidence interval: 0.47 to 0.67). Upon stratification by treatment types, teat sealants and combination therapies (vaccines and antimicrobials; antimicrobials and teat sealants; and all 3) were most effective at improving udder health with pooled risk ratios of 0.40 (95% confidence interval: 0.30 to 0.52) and 0.34 (95% confidence interval: 0.25 to 0.45), respectively. Antimicrobials and vaccines also reduced occurrence of IMI and subclinical and clinical mastitis when compared with untreated heifers. Although variation was observed in the pathogen-specific effectiveness of treatments at reducing rates of disease, antimicrobials, teat sealants, and combinations of vaccines or teat sealants with antimicrobials were consistently effective, whereas vaccines were only effective for contagious pathogens. Recommendations for use of antibiotics should consider their relative benefit while also considering potential for increasing antimicrobial resistance.

      Key words

      INTRODUCTION

      Mastitis is one of the most economically important diseases in the dairy industry (
      • Seegers H.
      • Fourichon C.
      • Beaudeau F.
      Production effects related to mastitis and mastitis economics in dairy cattle herds.
      ) as it has implications not only for animal health and welfare, but also for milk quality and production. The occurrence of mastitis is not only high in lactating cows, but also in heifers in the first weeks after calving (
      • De Vliegher S.
      • Fox L.K.
      • Piepers S.
      • McDougall S.
      • Barkema H.W.
      Invited review: Mastitis in dairy heifers: Nature of the disease, potential impact, prevention, and control.
      ;
      • Naqvi S.A.
      • De Buck J.
      • Dufour S.
      • Barkema H.W.
      Udder health in Canadian dairy heifers during early lactation.
      ). Heifers with (sub)clinical mastitis, IMI, or both are often not identified because they are not milked, and therefore their teats and milk typically are not examined (
      • De Vliegher S.
      • Fox L.K.
      • Piepers S.
      • McDougall S.
      • Barkema H.W.
      Invited review: Mastitis in dairy heifers: Nature of the disease, potential impact, prevention, and control.
      ). However, the prevalence of IMI in the months before the first calving is high, resulting in a high prevalence of heifers calving with IMI (
      • De Vliegher S.
      • Fox L.K.
      • Piepers S.
      • McDougall S.
      • Barkema H.W.
      Invited review: Mastitis in dairy heifers: Nature of the disease, potential impact, prevention, and control.
      ).
      Although nonlactating heifers are not included in standard mastitis prevention plans like the 5-point schedule (
      • Neave F.K.
      • Dodd F.H.
      • Kingwill R.G.
      • Westgarth D.R.
      Control of mastitis in the dairy herd by hygiene and management.
      ) or the relatively recent NMC 10-point plan (
      • National Mastitis Council (NMC)
      Recommended Mastitis Control Program.
      ), a variety of treatments to prevent or cure IMI in these heifers has been studied. Following a review on heifer mastitis (
      • De Vliegher S.
      • Fox L.K.
      • Piepers S.
      • McDougall S.
      • Barkema H.W.
      Invited review: Mastitis in dairy heifers: Nature of the disease, potential impact, prevention, and control.
      ), the NMC published a 10-point plan specifically for controlling heifer mastitis. In this new set of recommendations, only 2 were specific to heifers, whereas the others were similar to recommendations in the first 10-point plan. Some commonly used precalving treatments are vaccines, non-antimicrobial teat sealants, short- and long-term antimicrobials, and combinations of these treatments. Many studies have been conducted on effects of a single type of treatment in heifers (
      • Edinger D.
      • Tenhagen B.A.
      • Kalbe P.
      • Klunder G.
      • Baumgartner B.
      • Heuwieser W.
      Effect of teat dipping with a germicide barrier teat dip in late gestation on intramammary infection and clinical mastitis during the first 5 days post-partum in primiparous cows.
      ;
      • Santos J.E.P.
      • Cerri R.L.A.
      • Kirk J.H.
      • Juchem S.O.
      • Villasenor A.
      Effect of prepartum milking of primigravid cows on mammary gland health and lactation performance.
      ;
      • Roy J.P.
      • Du Tremblay D.
      • DesCôteaux L.
      • Messier S.
      • Scholl D.
      • Bouchard É.
      Effect of precalving intramammary treatment with pirlimycin in nulliparous Holstein heifers.
      ;
      • Pellegrino M.
      • Giraudo J.
      • Raspanti C.
      • Nagel R.
      • Odierno L.
      • Primo V.
      • Bogni C.
      Experimental trial in heifers vaccinated with Staphylococcus aureus avirulent mutant against bovine mastitis.
      ). However, very few studies have compared types of therapies, and their results have been inconsistent (
      • McDougall S.
      • Parker K.I.
      • Heuer C.
      • Compton C.W.R.
      A review of prevention and control of heifer mastitis via non-antibiotic strategies.
      ).
      Previous studies have demonstrated and quantified a net positive benefit of various precalving treatments (
      • Ataee O.
      • Hovareshti P.
      • Bolourchi M.
      • Barin A.
      • Gerami A.
      • Niasari-Naslaji A.
      Effect of systemic antibacterial administration during prepartum period on coagulase negative staphylococcal intramammary infection in Holstein heifers.
      ;
      • Duplessis M.
      • Girard C.L.
      • Santschi D.E.
      • Laforest J.P.
      • Durocher J.
      • Pellerin D.
      Effects of folic acid and vitamin B12 supplementation on culling rate, diseases, and reproduction in commercial dairy herds.
      ;
      • Passchyn P.
      • Piepers S.
      • De Vliegher S.
      Pathogen group-specific risk factors for intramammary infection in treated and untreated dairy heifers participating in a prepartum antimicrobial treatment trial.
      ), as well as characterizing pathogens causing ensuing infections. Systematic reviews have been conducted on the effectiveness of antimicrobial treatments in heifers (
      • Nickerson S.C.
      Control of heifer mastitis: Antimicrobial treatment—An overview.
      ), non-antibiotic strategies for prevention and control of mastitis in heifers (
      • McDougall S.
      • Parker K.I.
      • Heuer C.
      • Compton C.W.R.
      A review of prevention and control of heifer mastitis via non-antibiotic strategies.
      ), and vaccines for lactating cows (
      • Middleton J.R.
      • Luby C.D.
      • Adams D.S.
      Efficacy of vaccination against staphylococcal mastitis: A review and new data.
      ), whereas reviews of postpartum mastitis and mastitis control have also described preventive treatments in heifers and lactating cows (
      • Pyörälä S.
      Mastitis in post-partum dairy cows.
      ;
      • De Vliegher S.
      • Fox L.K.
      • Piepers S.
      • McDougall S.
      • Barkema H.W.
      Invited review: Mastitis in dairy heifers: Nature of the disease, potential impact, prevention, and control.
      ). However, no review has focused on quantifying treatment effectiveness in heifers, or compared efficacy of precalving treatment types using a meta-analysis to estimate overall effect size. Objectives of this study were therefore to (1) synthesize results from previous studies to determine and compare effectiveness of various types of precalving therapies aimed at improving udder health; and (2) determine and compare effectiveness of various types of precalving therapies against types of pathogens, grouped by etiology.

      MATERIALS AND METHODS

      This systematic review and meta-analysis was conducted following a pre-specified protocol created using the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines (
      • Shamseer L.
      • Moher D.
      • Clarke M.
      • Ghersi D.
      • Liberati A.
      • Petticrew M.
      • Shekelle P.
      • Stewart L.A.
      • PRISMA-P Group
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation.
      ).

      Data Sources and Literature Search

      Online databases searched were CAB Abstracts, Web of Science (complete collection), AGRICOLA, MedLine, and SCOPUS, from inception to September 2017. In addition, 2 individuals (SAN and DBN) hand-searched references of existing reviews on the subject. Gray literature consisted of a search through all available conference proceedings in relevant conferences, as well as websites of pharmaceutical companies and the Proceedings of the World Buiatrics Congress (2000–2014) on The International Veterinary Information Service website. In addition, proceedings of the American Dairy Science Association (1957–2017) and National Mastitis Council (NMC; 1989–2017) annual meetings were searched. Experts in the field were also contacted for information about potential ongoing or unpublished studies, and were identified through the review process or through direct communications at conferences (Mastitis Research Worker's meeting in November 2016, and NMC annual meeting in January 2017). No publication date or language filter was applied to the search, and the search was conducted as recommended (
      ).
      The search strategy was split into 3 main components corresponding to the population of interest, intervention type, and study outcome. The population of interest included primigravid to primiparous dairy cattle, with the intervention having to be applied during pregnancy and udder health measured after calving. The interventions of interest were any kind of treatment applied precalving aimed specifically at improving udder health. This was intended to exclude interventions such as feed additives intended to improve overall health and growth, as it did not address the primary question of targeted and individual treatment of heifers. Full details of the search terms used are provided (Appendix).

      Study Eligibility and Selection

      An initial screen of all titles was performed by 2 individuals (SAN and DBN) to determine if manuscripts were eligible for full text review for inclusion in the systematic review. If the title was not detailed enough to decide about moving forward with full-text screening, the abstract was scrutinized by one of the reviewers (SAN) to determine whether it was eligible. A manuscript needed to meet 2 conditions to be considered for a full text review: (1) The manuscript had to report on primary data; and (2) the manuscript had to report on an intervention aimed at improving udder health (no vaccines for other conditions such as leucosis, or treatment with anthelminthic products), although it may not necessarily be the primary aim of the study (comparing mastitis in 2 regions where a particular product may not be allowed).
      This initial screen was designed to be fairly broad to encompass as many potentially relevant manuscripts for full text review. A full text review was then conducted on all of these screened manuscripts to ensure that some aspect of intervention was addressed in the manuscript. The reason for this full text screening step in the systematic review was that the second condition described above could have resulted in manuscripts whose primary goal was not assessing intervention effectiveness, but was included as a covariate in their analysis. As it was not the primary goal of the study, it may not have been reported in the abstract and a full text screening would capture these manuscripts.

      Identification of Manuscripts for Eligibility in the Systematic Review and Meta-Analysis

      The same 2 individuals (SAN and DBN) reviewed full text manuscripts identified after the 2 screening stages described in the previous section using the following criteria to select manuscripts eligible for inclusion in the systematic review and meta-analysis.
      • d
        s
      • Population = primigravid/primiparous dairy cattle (if the primary study population was not primiparous dairy cattle, the manuscript must stratify and report on them separately from older animals).
      • Intervention = any sort of treatment given after confirmed pregnancy, before calving or on the day of calving that was aimed specifically at improving udder health. Studies that did not assess treatment effectiveness as a primary goal (described in the previous section) were excluded from the systematic review and meta-analysis because they would not be designed around that variable and pooling would not be appropriate.
      • Comparison = a treatment must be compared with either another treatment, or no treatment at all.
      • Outcome = postcalving prevalence or incidence of (1) clinical mastitis (CM); (2) subclinical mastitis (SCM; elevated SCC); or (3) IMI (presence of bacteria in the milk) reported within 2 mo after first calving.
      • Study design = randomized controlled trials or observational cohort studies.
      The screening of manuscripts was designed to capture studies comparing precalving treatments in heifers to each other or to untreated heifers in their association with incidence of udder disease postcalving. Only randomized controlled trials were meta-analyzed, whereas results from observational cohort studies were included descriptively in the discussion. Agreement between reviewers (SAN and DBN) regarding study inclusion was quantified using a kappa score and percent agreement, and any disagreements were resolved by the last author (HWB).

      Study Quality Assessment and Data Extraction

      Study quality and risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool (
      • Hooijmans C.R.
      • Rovers M.M.
      • De Vries R.B.
      • Leenaars M.
      • Ritskes-Hoitinga M.
      • Langendam M.W.
      SYRCLE's risk of bias tool for animal studies.
      ). The SYRCLE tool is based on the Cochrane Risk of Bias tool (
      2011. Assessing risk of bias in included studies.
      ), with some items modified or added to fit better with risk of bias in experimental trials in animals. Briefly, the SYRCLE tool consists of 10 items, corresponding to 5 types of bias: selection, performance, detection, attrition, and reporting bias. Risk of selection bias is evaluated through considering allocation sequence generation, subject baseline characteristics, and allocation concealments. Performance bias is evaluated by considering random housing of heifers and blinding when assigning treatments. Detection bias is assessed by evaluating randomization of subjects during outcome assessment and blinding of outcome assessors. Attrition bias is assessed by evaluating the study's reporting on incomplete outcome data. Lastly, reporting bias is assessed by evaluating outcomes on which studies reported, as well as outcomes that were excluded. A study was considered to be at high risk of a given type of bias if it had failed to address over half of the sources of error contributing to that given type; moderate risk of bias if they failed to address at least 1, but not more than half; and low or no risk of bias if they did not have any sources of error from a given type of bias.
      Data were extracted using a single electronic form using Microsoft Excel (Microsoft Corp., Redmond, WA). Study characteristics extracted were (1) country of study, (2) year of publication, (3) breed, (4) intervention type(s), and (5) time of intervention application. As management decisions are based on anticipated calving dates, the intended or median of intended application times was recorded in the extraction form (e.g., for 2 to 3 wk precalving, the number taken was 17.5 d). Outcome characteristics recorded, often multiple for a study, were (1) type of outcome defined as cure rate of existing IMI, SCM, IMI (and its definition), and CM; (2) time of outcome measurement or follow-up in the case of CM; and (3) numbers of individuals (animals or quarters depending on the study) and cases per treatment arm of the study. For studies where postcalving samples were collected on multiple days, the earliest sample that was not the day of calving was used for outcome extraction. Numbers in treatment arms were pooled by intervention or control and type of intervention depending on possible stratification in meta-analyses.

      Statistical Analyses

      All statistical analyses were performed using the “metafor” package (
      • Viechtbauer W.
      Conducting meta-analyses in R with the metafor package.
      ) in R version 3.4.2 (R Core Team 2017, R Foundation for Statistical Computing, Vienna, Austria). For all analyses, a P-value <0.05 was considered significant, and a 0.05 < P-value < 0.10 was considered a tendency for significance. Results from randomized clinical trials were pooled using a random-effects meta-analysis, as no observational studies were included in the systematic review. Randomized clinical trials that did not report numbers of individuals and only ratios were not included in the meta-analysis but were included only descriptively. A mixed effects model was selected given the underlying heterogeneity in intervention and population characteristics, and the fact that studies often had multiple treatment types and outcomes. Effect sizes were pooled as risk ratios (RR) because it is most intuitively interpretable in terms of detecting a benefit/harm. All pooled estimates and stratified meta-analyses were visualized using forest plots, and homogeneity was assessed using the Cochrane Q statistic for significance and I2 statistic to quantify the amount of variation due to study heterogeneity. The primary question concerning therapy type was statistically tested using meta-regression, and heterogeneity was then explored by stratifying on relevant variables of practical interest: type of outcome and bacterial species of infection. Variation in effectiveness by pathogen type was addressed through a combination of meta-regression and subgroup analyses. Sensitivity and specificity to detect IMI varies considerably among IMI definitions (
      • Andersen S.
      • Dohoo I.R.
      • Olde Riekerink R.
      • Stryhn H.
      Diagnosing intramammary infections: Evaluating expert opinions on the definition of intramammary infection using conjoint analysis.
      ;
      • Dohoo I.
      • Andersen S.
      • Dingwell R.
      • Hand K.
      • Kelton D.
      • Leslie K.
      • Schukken Y.
      • Godden S.
      Diagnosing intramammary infections: Comparison of multiple versus single quarter milk samples for the identification of intramammary infections in lactating dairy cows.
      ,
      • Dohoo I.R.
      • Smith J.
      • Andersen S.
      • Kelton D.F.
      • Godden S.
      Diagnosing intramammary infections: Evaluation of definitions based on a single milk sample.
      ), so a meta-regression was conducted to determine whether effect size estimates with rates of IMI differed between studies that described their IMI definition and those that only provided details for culturing. Questions related to effects of study quality or design (abstract versus full text, disease definitions) were also addressed using meta-regression. Publication bias for the primary outcome of interest (mastitis of any form) was assessed using a funnel plot of the RR with the standard error of the RR. Asymmetry was tested using Egger's regression test for small study effects, and visualized with a graph of study variance against the natural log of the RR.

      RESULTS

      Description of Studies

      Search Results

      Numbers of studies included at various stages of the review process are shown (Figure 1). Briefly, a total of 974 unique records were identified, with most coming from the database search (n = 1,245 before duplicate removal) and a small number being identified through the described gray literature review (n = 44 before duplicate removal). After screening abstracts, 82 peer-reviewed manuscripts were identified for a more thorough full-text review, along with 31 records from conference proceedings. A small number of non-English manuscripts were identified: Portuguese (n = 1), German (n = 3), Dutch (n = 1), Czech (n = 1), and Italian (n = 1). These manuscripts were reviewed using the pre-specified criteria by colleagues with fluency in the respective languages.
      Figure thumbnail gr1
      Figure 1Flow diagram of the manuscript selection process. ADSA = American Dairy Science Association; NMC = National Mastitis Council.

      Studies Eligible for Inclusion in the Systematic Review

      Forty studies from published manuscripts were included in the systematic review, of which 38 were eligible for inclusion in the meta-analysis. All included peer-reviewed manuscripts reported results from clinical trials; 2 could not be included in the meta-analysis because they did not report numbers of outcomes, rather relative measures such as RR and odds ratios. In addition, 22 studies from conference proceedings or abstracts were included in the systematic review. Ten conference proceedings provided enough detail in their results to be eligible for meta-analysis, whereas others were discussed only descriptively. Records from 48 studies were included in the meta-analysis, although multiple records were included for many studies because they compared multiple treatment types (Table 1). A detailed description of the specific products used in each study is provided (Appendix Table A1).
      Table 1Study characteristics of the 62 included studies
      Type of intervention studied: AM = antimicrobial; TSE = teat sealant; TD = teat dips/sprays; VAC = vaccine; COM = combination of multiple types. Intended application time for intervention was based on expected parturition date; actual time relative to calving was variable. Outcomes reported on the following: CM = clinical mastitis; SCM = subclinical mastitis; CR = cure rate of existing infections.
      ReferenceCountryHeifer breedIntervention typeTime of intervention application (d before calving)Outcome typeOutcome measurement time (DIM)Pathogens studied
      Presented if the study differentiated infectious pathogens. Cont. = contagious; Env. = environmental.
      AMTSETDOtherVACCOMCMIMISCMCRCont.CNSEnv.

      Acuña, C. N., and R. E. Chertcoff. 2003. Mastitis control program on dairies with high incidence in first calving heifers: Part 2. In Proc. 42nd NMC Annu. Mtg.

      Inclusion and analysis based on abstract or conference proceedings.
      Not included in meta-analysis.
      ArgentinaHolando Argentino453
      • Acuña C.N.
      • Casasnovas G.F.
      • Terminiello S.
      • Moreno A.
      • Santarcangelo C.G.
      • Simon L.O.
      Use of dry cow therapy with internal teat sealant for the prevention of clinical mastitis occurring after calving in heifers with Staphylococcus aureus.
      Inclusion and analysis based on abstract or conference proceedings.
      ArgentinaHolando Argentino6030
      • Acuña Pasqualini C.N.
      • Casasnovas G.F.
      • Macazaga C.F.
      Effectiveness in the reduction of new intramammary infections in the dry period by the use of an external teat sealant in heifers at prepartum.
      Inclusion and analysis based on abstract or conference proceedings.
      ArgentinaHolstein123–6
      • Alaniz G.R.
      • Meinert T.R.
      • Loveland W.J.
      • Gallo G.
      • Salmon S.A.
      Evaluation of Escherichia coli bacterin, J-5 strain, as an aid in the control of clinical signs associated with E. coli mastitis in dairy cows.
      Inclusion and analysis based on abstract or conference proceedings.
      Not included in meta-analysis.
      USMixed7521
      • Ataee O.
      • Hovareshti P.
      • Bolourchi M.
      • Barin A.
      • Gerami A.
      • Niasari-Naslaji A.
      Effect of systemic antibacterial administration during prepartum period on coagulase negative staphylococcal intramammary infection in Holstein heifers.
      IranHolstein10–143
      • Barto P.B.
      • Bush L.J.
      Effect of prepartum antibiotic infusion on mastitis infection in dairy cows at first calving.
      USMixed10–143
      • Bassel L.
      • Kelton D.
      • Godkin A.
      • Leslie K.
      • Lissemore K.
      Risk factors for intramammary infection at first calving in heifers from Ontario sentinel herds.
      Inclusion and analysis based on abstract or conference proceedings.
      Not included in meta-analysis.
      CanadaMixed1
      • Bastan A.
      • Cengiz M.
      • Cengiz S.
      • Polat B.
      • Colak A.
      • Akan M.
      • Darbaz I.
      • Acar D.B.
      Effects of precalving antibiotic treatment on mastitis and individual somatic cell count in heifers.
      TurkeyHolstein4510
      • Borm A.A.
      • Fox L.K.
      • Leslie K.E.
      • Hogan J.S.
      • Andrew S.M.
      • Moyes K.M.
      • Oliver S.P.
      • Schukken Y.H.
      • Hancock D.D.
      • Gaskins C.T.
      • Owens W.E.
      • Norman C.
      Effects of prepartum intramammary antibiotic therapy on udder health, milk production, and reproductive performance in dairy heifers.
      US/Canada10–214
      • Bowers S.
      • Gandy S.
      • Graves K.
      • Eicher S.
      • Willard S.
      Effects of prepartum milking on postpartum reproduction, udder health and production performance in first-calf dairy heifers.
      USMixedStarting at 21Up to 60
      • Bray D.R.
      • Elvinger F.
      • de la Sota R.L.
      • Natzke R.P.
      • Reed P.A.
      • Shearer J.K.
      Prevalence of infection in mammary quarters of nulliparous heifers and efficacy of intra-mammary infusion of antibiotics three weeks before parturition.
      Inclusion and analysis based on abstract or conference proceedings.
      US211
      • Bryan M.A.
      • Friton G.M.
      Stochastic economic modeling of the use of penethamate hydriodide (Mamyzin®) in heifers around calving to control peri-parturient mastitis.
      New Zealand04
      • Bryan M.
      • Taylor K.
      Periparturient use of parenteral micronised procaine penicillin to reduce the risk of clinical mastitis in heifers after calving.
      New Zealand04
      • Bush L.J.
      • Barto P.B.
      • Adams G.D.
      Effect of teat dipping on mastitis infection in dairy heifers at 1st calving.
      USMixed144
      • Compton C.
      • McDougall S.
      Effect of early milking of calved heifers and selenium supplementation on incidence of clinical mastitis in dairy heifers.
      Inclusion and analysis based on abstract or conference proceedings.
      New Zealand04–21
      • Compton C.W.R.
      • Emslie F.R.
      • McDougall S.
      Randomised controlled trials demonstrate efficacy of a novel internal teat sealant to prevent new intramammary infections in dairy cows and heifers.
      New ZealandMixed213 for IMI; 30 for CM
      • Contreras G.A.
      • David Munoz J.
      • Sears P.M.
      Reducing the incidence of intramammary infection in heifers by using prepartum systemic tylosin therapy: Initial results of a single herd pilot study.
      US12–184
      • Edinger D.
      • Tenhagen B.A.
      • Kalbe P.
      • Klunder G.
      • Baumgartner B.
      • Heuwieser W.
      Effect of teat dipping with a germicide barrier teat dip in late gestation on intramammary infection and clinical mastitis during the first 5 days post-partum in primiparous cows.
      GermanyHolsteinStarting at 154
      • Galphin S.P.
      • Patrick E.
      Evaluation of insecticide impregnated tail tags for preventing intramammary infection in dairy heifers.
      Inclusion and analysis based on abstract or conference proceedings.
      USHolstein3000
      • Gentilini M.B.
      • Molina L.R.
      • Carvalho A.U.
      Use of an Escherichia coli J5 vaccine on immunization of dairy heifers against mastitis caused by E. coli..
      BrazilMixed607 for IMI; 100 for CM
      • Gilbert D.
      Use of internal teat sealants in pre calving heifers to control early lactational mastitis in UK.
      Inclusion and analysis based on abstract or conference proceedings.
      Wales6030
      • Giraudo J.A.
      • Calzolari A.
      • Rampone H.
      • Rampone A.
      • Giraudo A.T.
      • Bogni C.
      • Larriestra A.
      • Nagel R.
      Field trials of a vaccine against bovine mastitis. 1. Evaluation in heifers.
      ArgentinaHolstein5615
      • Han H.R.
      • Park H.M.
      A field trial with a bovine staphylococcal mastitis vaccine in lactating cows and heifers.
      Inclusion and analysis based on abstract or conference proceedings.
      Korea
      • Hovareshti P.
      • Bolourchi M.
      • Tabatabayi A.H.
      Comparison of the effect of systemic and local antibacterial therapy to control staphylococcal intramammary infection in prepartum heifers.
      IranHolstein7–147–14
      • Jimenez L.
      • Timon R.
      • Marco J.
      Effect of Cefalonium on intramammary infections and on milk production of heifers before their first calving.
      Inclusion and analysis based on abstract or conference proceedings.
      Spain607
      • Lopez-Benavides M.G.
      • Cursons R.T.
      • Lacy-Hulbert S.J.
      • Williamson J.H.
      Heifer teats sprayed in the dry period with an iodine teat sanitizer have reduced Streptococcus uberis teat-end contamination and less Streptococcus uberis intra-mammary infections at calving.
      New ZealandStarting at 2114
      • Lopez-Benavides M.G.
      • Williamson J.H.
      • Lacy-Hulbert S.J.
      • Cursons R.T.
      Teat spraying prior to calving may reduce the risk of heifer mastitis caused by Streptococcus uberis..
      New ZealandStarting at 2114
      • Matthews K.R.
      • Harmon R.J.
      • Langlois B.E.
      • Crist W.L.
      • Hemken R.W.
      Use of latex teat dip with germicide during the prepartum period.
      USMixed148
      • McCarthy K.K.
      • Kreft R.
      • Sears P.M.
      Effect of prepartum intramammary treatment in heifers on postpartum intramammary infections, somatic cell count and milk production.
      Inclusion and analysis based on abstract or conference proceedings.
      Not included in meta-analysis.
      US215
      • McDougall S.
      • Parker K.I.
      • Weir A.M.
      • Compton C.W.R.
      Effect of application of an external teat sealant and/or oral treatment with a monensin capsule precalving on the prevalence and incidence of subclinical and clinical mastitis in dairy heifers.
      New Zealand2110
      • McDougall S.
      • Parker K.
      • Compton C.
      • Heuer C.
      Reducing subclinical and clinical mastitis in dairy heifers by precalving infusion of a teat sealant and/or parenteral antibiotic therapy.
      Not included in meta-analysis.
      New ZealandMixed404 for IMI; 14 for CM
      • Middleton J.R.
      • Luby C.D.
      • Steevens B.J.
      • Lakritz J.
      • Timms L.L.
      • Bader G.R.
      Effect of prepartum intramammary treatment with pirlimycin hydrochloride on prevalence of early first-lactation mastitis in dairy heifers.
      USHolstein10–147–28
      • Newton H.
      • Chambers G.
      Incidence of peri-calving clinical mastitis in maiden heifers treated with an internal teat sealant at varying precalving intervals.
      Inclusion and analysis based on abstract or conference proceedings.
      New Zealand28
      • Lopez-Benavides M.G.
      • Williamson J.H.
      • Lacy-Hulbert S.J.
      • Cursons R.T.
      Teat spraying prior to calving may reduce the risk of heifer mastitis caused by Streptococcus uberis..
      New ZealandStarting at 2114
      • Edinger D.
      • Tenhagen B.A.
      • Kalbe P.
      • Klunder G.
      • Baumgartner B.
      • Heuwieser W.
      Effect of teat dipping with a germicide barrier teat dip in late gestation on intramammary infection and clinical mastitis during the first 5 days post-partum in primiparous cows.
      GermanyHolsteinStarting at 154
      • Galphin S.P.
      • Patrick E.
      Evaluation of insecticide impregnated tail tags for preventing intramammary infection in dairy heifers.
      Inclusion and analysis based on abstract or conference proceedings.
      USHolstein3000
      • Gentilini M.B.
      • Molina L.R.
      • Carvalho A.U.
      Use of an Escherichia coli J5 vaccine on immunization of dairy heifers against mastitis caused by E. coli..
      BrazilMixed607 for IMI; 100 for CM
      • Gilbert D.
      Use of internal teat sealants in pre calving heifers to control early lactational mastitis in UK.
      Inclusion and analysis based on abstract or conference proceedings.
      Wales6030
      • Giraudo J.A.
      • Calzolari A.
      • Rampone H.
      • Rampone A.
      • Giraudo A.T.
      • Bogni C.
      • Larriestra A.
      • Nagel R.
      Field trials of a vaccine against bovine mastitis. 1. Evaluation in heifers.
      ArgentinaHolstein5615
      • Han H.R.
      • Park H.M.
      A field trial with a bovine staphylococcal mastitis vaccine in lactating cows and heifers.
      Inclusion and analysis based on abstract or conference proceedings.
      Korea
      • Hovareshti P.
      • Bolourchi M.
      • Tabatabayi A.H.
      Comparison of the effect of systemic and local antibacterial therapy to control staphylococcal intramammary infection in prepartum heifers.
      IranHolstein7–147–14
      • Jimenez L.
      • Timon R.
      • Marco J.
      Effect of Cefalonium on intramammary infections and on milk production of heifers before their first calving.
      Inclusion and analysis based on abstract or conference proceedings.
      Spain607
      • Lopez-Benavides M.G.
      • Cursons R.T.
      • Lacy-Hulbert S.J.
      • Williamson J.H.
      Heifer teats sprayed in the dry period with an iodine teat sanitizer have reduced Streptococcus uberis teat-end contamination and less Streptococcus uberis intra-mammary infections at calving.
      New ZealandStarting at 2114
      • Lopez-Benavides M.G.
      • Williamson J.H.
      • Lacy-Hulbert S.J.
      • Cursons R.T.
      Teat spraying prior to calving may reduce the risk of heifer mastitis caused by Streptococcus uberis..
      New ZealandStarting at 2114
      • Matthews K.R.
      • Harmon R.J.
      • Langlois B.E.
      • Crist W.L.
      • Hemken R.W.
      Use of latex teat dip with germicide during the prepartum period.
      USMixed148
      • McCarthy K.K.
      • Kreft R.
      • Sears P.M.
      Effect of prepartum intramammary treatment in heifers on postpartum intramammary infections, somatic cell count and milk production.
      Inclusion and analysis based on abstract or conference proceedings.
      Not included in meta-analysis.
      US215
      • McDougall S.
      • Parker K.I.
      • Weir A.M.
      • Compton C.W.R.
      Effect of application of an external teat sealant and/or oral treatment with a monensin capsule precalving on the prevalence and incidence of subclinical and clinical mastitis in dairy heifers.
      New Zealand2110
      • McDougall S.
      • Parker K.
      • Compton C.
      • Heuer C.
      Reducing subclinical and clinical mastitis in dairy heifers by precalving infusion of a teat sealant and/or parenteral antibiotic therapy.
      Not included in meta-analysis.
      New ZealandMixed404 for IMI; 14 for CM
      • Middleton J.R.
      • Luby C.D.
      • Steevens B.J.
      • Lakritz J.
      • Timms L.L.
      • Bader G.R.
      Effect of prepartum intramammary treatment with pirlimycin hydrochloride on prevalence of early first-lactation mastitis in dairy heifers.
      USHolstein10–147–28
      • Newton H.
      • Chambers G.
      Incidence of peri-calving clinical mastitis in maiden heifers treated with an internal teat sealant at varying precalving intervals.
      Inclusion and analysis based on abstract or conference proceedings.
      New Zealand28
      • Nickerson S.C.
      • Boddie R.L.
      Effects of novel intramammary devices on incidence of mastitis.
      Inclusion and analysis based on abstract or conference proceedings.
      Not included in meta-analysis.
      US
      • Nickerson S.C.
      • Owens W.E.
      • Boddie R.L.
      Mastitis in dairy heifers: A historical review.
      Inclusion and analysis based on abstract or conference proceedings.
      Not included in meta-analysis.
      US
      • Nickerson S.C.
      • Owens W.E.
      • Tomita G.M.
      • Widel P.W.
      Vaccinating dairy heifers with a Staphylococcus aureus bacterin reduces mastitis at calving.
      USJersey5400
      • Nickerson S.C.
      • Hovingh E.P.
      • Widel P.W.
      Immunisation of dairy heifers with a Staphylococcus aureus bacterin reduces infection level and somatic cell counts at time of calving.
      USHolstein3650
      • Norman C.B.
      • Owens W.E.
      • Boddie R.L.
      • Ray C.H.
      Efficacy of prepartum, intramammary lactating cow antibiotics in dairy heifers.
      Inclusion and analysis based on abstract or conference proceedings.
      Not included in meta-analysis.
      USMixed1414
      • Oliver S.P.
      • King S.H.
      • Lewis M.J.
      • Dowlen H.H.
      Influence of prepartum antibiotic therapy on intramammary infections (IMI) in primigravid heifers during early lactation.
      USJersey77
      • Oliver S.P.
      • Lewis M.J.
      • Gillespie B.E.
      • Dowlen H.H.
      Antibiotic residues and prevalence of mastitis pathogen isolation in heifers during early lactation following prepartum antibiotic therapy.
      USJersey143
      • Oliver S.P.
      • Lewis M.J.
      • Gillespie B.E.
      • Dowlen H.H.
      Influence of prepartum antibiotic administration on intramammary infections in multiparous dairy cows during early lactation.
      Inclusion and analysis based on abstract or conference proceedings.
      Not included in meta-analysis.
      USMixed00
      • Oliver S.P.
      • Jaenicke E.C.
      • Roberts R.K.
      • Dowlen H.H.
      • Lewis M.J.
      • Gillespie B.E.
      Prepartum antibiotic treatment of heifers: Milk production, milk quality and economic benefit.
      USJersey73
      • Oliver S.P.
      • Dowlen H.H.
      • Moorehead H.
      • Hallberg J.W.
      • Chester S.T.
      • Lamar K.C.
      • Ivey S.J.
      • Gillespie B.E.
      • Johnson D.L.
      • Lewis M.J.
      Influence of prepartum pirlimycin hydrochloride or penicillin-novobiocin therapy on mastitis in heifers during early lactation.
      USMixed147, 14, 30
      • Oliver S.P.
      • Headrick S.I.
      • Gillespie B.E.
      • Lewis M.J.
      • Johnson D.L.
      • Lamar K.C.
      • Moorehead H.
      • Dowlen H.H.
      • Hallberg J.W.
      Intramammary infections in heifers during early lactation following intramammary infusion of pirlimycin hydrochloride or penicillin-novobiocin at the first milking after parturition.
      USMixed030
      • Owens W.E.
      • Nickerson S.C.
      • Boddie R.L.
      • Tomita G.M.
      • Ray C.H.
      Prevalence of mastitis in dairy heifers and effectiveness of antibiotic therapy.
      USJersey1st, 2nd, and 3rd trimesters0
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougall S.
      Subclinical and clinical mastitis in heifers following the use of a teat sealant precalving.
      New Zealand304
      • Parker K.I.
      • Heuer C.
      • McDougall S.
      • Compton C.W.R.
      • Anniss F.M.
      Quarter-level analysis of subclinical and clinical mastitis in primiparous heifers following the use of a teat sealant or an injectable antibiotic, or both, precalving.
      New Zealand305
      • Passchyn P.
      • Piepers S.
      • De Vliegher S.
      Systemic prepartum treatment of end-term dairy heifers with penethamate hydriodide: Effect on udder health, milk yield, and culling until 120 days in milk.
      Belgium143
      • Pellegrino M.
      • Giraudo J.
      • Raspanti C.
      • Nagel R.
      • Odierno L.
      • Primo V.
      • Bogni C.
      Experimental trial in heifers vaccinated with Staphylococcus aureus avirulent mutant against bovine mastitis.
      ArgentinaHolando ArgentinoPrepregnancy51
      • Pellegrino M.
      • Giraudo J.
      • Raspanti C.
      • Odierno L.
      • Bogni C.
      Efficacy of immunization against bovine mastitis using a Staphylococcus aureus avirulent mutant vaccine.
      ArgentinaHolando Argentino3021
      • Pol M.
      • Ebinger M.
      • Castelletti A.
      Efficacy of precalving treatment with parenteral danofloxacin in heifers.
      Inclusion and analysis based on abstract or conference proceedings.
      Argentina1550
      • Robertson B.G.
      • Williamson J.H.
      • Kuhn-Sherlock B.
      • Lacy-Hulbert S.J.
      • Turner S.A.
      Use of internal teat sealant in heifers reduces mastitis and may affect milk production.
      Not included in meta-analysis.
      New Zealand301 for IMI; 30 for CM; 56 for SCM
      • Roger N.
      • Jiménez L.M.
      Case study: Udder health in heifers after vaccination against mastitis.
      Inclusion and analysis based on abstract or conference proceedings.
      Not included in meta-analysis.
      SpainHolstein45
      • Roy J.P.
      • Du Tremblay D.
      • DesCôteaux L.
      • Messier S.
      • Scholl D.
      • Bouchard É.
      Effect of precalving intramammary treatment with pirlimycin in nulliparous Holstein heifers.
      CanadaHolstein95
      • Sampimon O.C.
      • de Vliegher S.
      • Barkema H.W.
      • Sol J.
      • Lam T.J.G.M.
      Effect of prepartum dry cow antibiotic treatment in dairy heifers on udder health and milk production.
      the NetherlandsHolstein6310
      • Santos J.E.P.
      • Cerri R.L.A.
      • Kirk J.H.
      • Juchem S.O.
      • Villasenor A.
      Effect of prepartum milking of primigravid cows on mammary gland health and lactation performance.
      USHolstein1528 for IMI; 135 for CM
      • Tenhagen B.A.
      • Edinger D.
      • Baumgartner B.
      • Kalbe P.
      • Klunder G.
      • Heuwieser W.
      Efficacy of a herd-specific vaccine against Staphylococcus aureus to prevent post-partum mastitis in dairy heifers.
      GermanyHolstein3521–28 for IMI; 90 for CM
      • Timms L.L.
      • Steffens A.
      • Allen L.
      Field trial evaluation of a persistent barrier teat dip for preventing mastitis during the dry period.
      Inclusion and analysis based on abstract or conference proceedings.
      Not included in meta-analysis.
      US123
      • Toušová R.
      • Stádník L.
      • Ducháček J.
      • Baráková M.
      Influence of vaccination against mastitis on its incidence, somatic cells amount and content of solid components in milk of primiparous dairy cows.
      Czech RepublicHolstein45
      • Trinidad P.
      • Nickerson S.C.
      Prevalence and treatment of intramammary infections in breeding age and in pregnant dairy heifers.
      Inclusion and analysis based on abstract or conference proceedings.
      Not included in meta-analysis.
      US180–900
      • Trinidad P.
      • Nickerson S.C.
      • Alley T.K.
      • Adkinson R.W.
      Efficacy of intramammary treatment in unbred and primigravid dairy heifers.
      Inclusion and analysis based on abstract or conference proceedings.
      Jersey0
      • Vargas R.T.
      • Souza F.N.
      • Brito M.A.V.P.
      • Brito J.R.F.
      • Leite M.O.
      • Fonseca L.M.
      • Sampaio I.B.M.
      • Cerqueira M.M.O.P.
      Partial budget analysis of prepartum antimicrobial therapy and Escherichia coli J5 vaccination of dairy heifers and their effect on milk production and milk quality parameters.
      BrazilHolstein60190
      1 Type of intervention studied: AM = antimicrobial; TSE = teat sealant; TD = teat dips/sprays; VAC = vaccine; COM = combination of multiple types. Intended application time for intervention was based on expected parturition date; actual time relative to calving was variable. Outcomes reported on the following: CM = clinical mastitis; SCM = subclinical mastitis; CR = cure rate of existing infections.
      2 Presented if the study differentiated infectious pathogens. Cont. = contagious; Env. = environmental.
      3 Inclusion and analysis based on abstract or conference proceedings.
      4 Not included in meta-analysis.

      Risk of Bias in Studies Included

      Design characteristics of all full-text manuscripts that are important for risk of bias are described (Table 2). Based on the SYRCLE guidelines, all studies were at high risk for at least one type of bias. The majority of studies were at moderate risk of selection bias (n = 27), with 2 being at low/no risk of selection bias. Allocation sequence generation was often systematic rather than completely random, and baseline animal characteristics were described in most studies (n = 30). The largest type of bias that this pool of studies was at risk for was detection/performance bias, as most did not describe blinding or randomized animal housing. Most (n = 31) studies adequately addressed incomplete data by providing numbers of heifers at each stage of the study, with reasons provided for their removal or exclusion from the trial minimizing risk of attrition bias. No studies were at risk of reporting bias, as they all either provided justification for outcomes measured or they were selected in part based on their reporting of outcomes.
      Table 2Risk of bias as assessed by Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) guidelines (Hooijmans et al., 2013) from full-text manuscripts included in systematic review (n = 40)
      A check mark indicates that the feature was thoroughly described and minimized risk of bias in that area.
      ReferenceSelection biasDetection and performance biasAttrition biasReporting bias
      Allocation concealmentAllocation implementationSequence generationBaseline characteristicsBlindingRandom housingRandom outcome assessmentIncomplete outcome dataSelective outcome reporting
      • Ataee O.
      • Hovareshti P.
      • Bolourchi M.
      • Barin A.
      • Gerami A.
      • Niasari-Naslaji A.
      Effect of systemic antibacterial administration during prepartum period on coagulase negative staphylococcal intramammary infection in Holstein heifers.
      • Barto P.B.
      • Bush L.J.
      Effect of prepartum antibiotic infusion on mastitis infection in dairy cows at first calving.
      • Bastan A.
      • Cengiz M.
      • Cengiz S.
      • Polat B.
      • Colak A.
      • Akan M.
      • Darbaz I.
      • Acar D.B.
      Effects of precalving antibiotic treatment on mastitis and individual somatic cell count in heifers.
      • Borm A.A.
      • Fox L.K.
      • Leslie K.E.
      • Hogan J.S.
      • Andrew S.M.
      • Moyes K.M.
      • Oliver S.P.
      • Schukken Y.H.
      • Hancock D.D.
      • Gaskins C.T.
      • Owens W.E.
      • Norman C.
      Effects of prepartum intramammary antibiotic therapy on udder health, milk production, and reproductive performance in dairy heifers.
      • Bowers S.
      • Gandy S.
      • Graves K.
      • Eicher S.
      • Willard S.
      Effects of prepartum milking on postpartum reproduction, udder health and production performance in first-calf dairy heifers.
      • Bryan M.A.
      • Friton G.M.
      Stochastic economic modeling of the use of penethamate hydriodide (Mamyzin®) in heifers around calving to control peri-parturient mastitis.
      • Bryan M.
      • Taylor K.
      Periparturient use of parenteral micronised procaine penicillin to reduce the risk of clinical mastitis in heifers after calving.
      • Bush L.J.
      • Barto P.B.
      • Adams G.D.
      Effect of teat dipping on mastitis infection in dairy heifers at 1st calving.
      • Compton C.W.R.
      • Emslie F.R.
      • McDougall S.
      Randomised controlled trials demonstrate efficacy of a novel internal teat sealant to prevent new intramammary infections in dairy cows and heifers.
      • Contreras G.A.
      • David Munoz J.
      • Sears P.M.
      Reducing the incidence of intramammary infection in heifers by using prepartum systemic tylosin therapy: Initial results of a single herd pilot study.
      • Edinger D.
      • Tenhagen B.A.
      • Kalbe P.
      • Klunder G.
      • Baumgartner B.
      • Heuwieser W.
      Effect of teat dipping with a germicide barrier teat dip in late gestation on intramammary infection and clinical mastitis during the first 5 days post-partum in primiparous cows.
      • Gentilini M.B.
      • Molina L.R.
      • Carvalho A.U.
      Use of an Escherichia coli J5 vaccine on immunization of dairy heifers against mastitis caused by E. coli..
      • Giraudo J.A.
      • Calzolari A.
      • Rampone H.
      • Rampone A.
      • Giraudo A.T.
      • Bogni C.
      • Larriestra A.
      • Nagel R.
      Field trials of a vaccine against bovine mastitis. 1. Evaluation in heifers.
      • Hovareshti P.
      • Bolourchi M.
      • Tabatabayi A.H.
      Comparison of the effect of systemic and local antibacterial therapy to control staphylococcal intramammary infection in prepartum heifers.
      • Lopez-Benavides M.G.
      • Cursons R.T.
      • Lacy-Hulbert S.J.
      • Williamson J.H.
      Heifer teats sprayed in the dry period with an iodine teat sanitizer have reduced Streptococcus uberis teat-end contamination and less Streptococcus uberis intra-mammary infections at calving.
      • Lopez-Benavides M.G.
      • Williamson J.H.
      • Lacy-Hulbert S.J.
      • Cursons R.T.
      Teat spraying prior to calving may reduce the risk of heifer mastitis caused by Streptococcus uberis..
      • Matthews K.R.
      • Harmon R.J.
      • Langlois B.E.
      • Crist W.L.
      • Hemken R.W.
      Use of latex teat dip with germicide during the prepartum period.
      • McDougall S.
      • Parker K.I.
      • Weir A.M.
      • Compton C.W.R.
      Effect of application of an external teat sealant and/or oral treatment with a monensin capsule precalving on the prevalence and incidence of subclinical and clinical mastitis in dairy heifers.
      • McDougall S.
      • Parker K.
      • Compton C.
      • Heuer C.
      Reducing subclinical and clinical mastitis in dairy heifers by precalving infusion of a teat sealant and/or parenteral antibiotic therapy.
      • Middleton J.R.
      • Luby C.D.
      • Steevens B.J.
      • Lakritz J.
      • Timms L.L.
      • Bader G.R.
      Effect of prepartum intramammary treatment with pirlimycin hydrochloride on prevalence of early first-lactation mastitis in dairy heifers.
      • Nickerson S.C.
      • Owens W.E.
      • Tomita G.M.
      • Widel P.W.
      Vaccinating dairy heifers with a Staphylococcus aureus bacterin reduces mastitis at calving.
      • Nickerson S.C.
      • Hovingh E.P.
      • Widel P.W.
      Immunisation of dairy heifers with a Staphylococcus aureus bacterin reduces infection level and somatic cell counts at time of calving.
      • Oliver S.P.
      • King S.H.
      • Lewis M.J.
      • Dowlen H.H.
      Influence of prepartum antibiotic therapy on intramammary infections (IMI) in primigravid heifers during early lactation.
      • Oliver S.P.
      • Lewis M.J.
      • Gillespie B.E.
      • Dowlen H.H.
      Antibiotic residues and prevalence of mastitis pathogen isolation in heifers during early lactation following prepartum antibiotic therapy.
      • Oliver S.P.
      • Jaenicke E.C.
      • Roberts R.K.
      • Dowlen H.H.
      • Lewis M.J.
      • Gillespie B.E.
      Prepartum antibiotic treatment of heifers: Milk production, milk quality and economic benefit.
      • Oliver S.P.
      • Dowlen H.H.
      • Moorehead H.
      • Hallberg J.W.
      • Chester S.T.
      • Lamar K.C.
      • Ivey S.J.
      • Gillespie B.E.
      • Johnson D.L.
      • Lewis M.J.
      Influence of prepartum pirlimycin hydrochloride or penicillin-novobiocin therapy on mastitis in heifers during early lactation.
      • Oliver S.P.
      • Headrick S.I.
      • Gillespie B.E.
      • Lewis M.J.
      • Johnson D.L.
      • Lamar K.C.
      • Moorehead H.
      • Dowlen H.H.
      • Hallberg J.W.
      Intramammary infections in heifers during early lactation following intramammary infusion of pirlimycin hydrochloride or penicillin-novobiocin at the first milking after parturition.
      • Owens W.E.
      • Nickerson S.C.
      • Boddie R.L.
      • Tomita G.M.
      • Ray C.H.
      Prevalence of mastitis in dairy heifers and effectiveness of antibiotic therapy.
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougall S.
      Subclinical and clinical mastitis in heifers following the use of a teat sealant precalving.
      • Parker K.I.
      • Heuer C.
      • McDougall S.
      • Compton C.W.R.
      • Anniss F.M.
      Quarter-level analysis of subclinical and clinical mastitis in primiparous heifers following the use of a teat sealant or an injectable antibiotic, or both, precalving.
      • Passchyn P.
      • Piepers S.
      • De Vliegher S.
      Systemic prepartum treatment of end-term dairy heifers with penethamate hydriodide: Effect on udder health, milk yield, and culling until 120 days in milk.
      • Pellegrino M.
      • Giraudo J.
      • Raspanti C.
      • Nagel R.
      • Odierno L.
      • Primo V.
      • Bogni C.
      Experimental trial in heifers vaccinated with Staphylococcus aureus avirulent mutant against bovine mastitis.
      • Pellegrino M.
      • Giraudo J.
      • Raspanti C.
      • Odierno L.
      • Bogni C.
      Efficacy of immunization against bovine mastitis using a Staphylococcus aureus avirulent mutant vaccine.
      • Robertson B.G.
      • Williamson J.H.
      • Kuhn-Sherlock B.
      • Lacy-Hulbert S.J.
      • Turner S.A.
      Use of internal teat sealant in heifers reduces mastitis and may affect milk production.
      • Roy J.P.
      • Du Tremblay D.
      • DesCôteaux L.
      • Messier S.
      • Scholl D.
      • Bouchard É.
      Effect of precalving intramammary treatment with pirlimycin in nulliparous Holstein heifers.
      • Sampimon O.C.
      • de Vliegher S.
      • Barkema H.W.
      • Sol J.
      • Lam T.J.G.M.
      Effect of prepartum dry cow antibiotic treatment in dairy heifers on udder health and milk production.
      • Santos J.E.P.
      • Cerri R.L.A.
      • Kirk J.H.
      • Juchem S.O.
      • Villasenor A.
      Effect of prepartum milking of primigravid cows on mammary gland health and lactation performance.
      • Tenhagen B.A.
      • Edinger D.
      • Baumgartner B.
      • Kalbe P.
      • Klunder G.
      • Heuwieser W.
      Efficacy of a herd-specific vaccine against Staphylococcus aureus to prevent post-partum mastitis in dairy heifers.
      • Toušová R.
      • Stádník L.
      • Ducháček J.
      • Baráková M.
      Influence of vaccination against mastitis on its incidence, somatic cells amount and content of solid components in milk of primiparous dairy cows.
      • Vargas R.T.
      • Souza F.N.
      • Brito M.A.V.P.
      • Brito J.R.F.
      • Leite M.O.
      • Fonseca L.M.
      • Sampaio I.B.M.
      • Cerqueira M.M.O.P.
      Partial budget analysis of prepartum antimicrobial therapy and Escherichia coli J5 vaccination of dairy heifers and their effect on milk production and milk quality parameters.
      1 A check mark indicates that the feature was thoroughly described and minimized risk of bias in that area.
      Another aspect of variability among studies and a possible source of bias was how they defined outcomes (Table 3), IMI in particular. Many studies (n = 16) only described culturing details for their milk samples, without a strict definition of what was considered an IMI. Risk ratio for IMI did not differ between treated and untreated heifers when comparing the 2 groups of studies (P = 0.93). Definition of IMI was not used in any subsequent analyses, or considered for stratification.
      Table 3Outcome definitions in full-text manuscripts included in the systematic review (n = 40)
      ReferenceOutcomes defined
      T = definitions were thoroughly described; P = definitions were partially described.
      Outcome definition
      SCM = subclinical mastitis; CM = clinical mastitis.
      • Ataee O.
      • Hovareshti P.
      • Bolourchi M.
      • Barin A.
      • Gerami A.
      • Niasari-Naslaji A.
      Effect of systemic antibacterial administration during prepartum period on coagulase negative staphylococcal intramammary infection in Holstein heifers.
      Culturing protocol only [National Mastitis Council (NMC) guidelines]
      • Barto P.B.
      • Bush L.J.
      Effect of prepartum antibiotic infusion on mastitis infection in dairy cows at first calving.
      Culturing protocol only (NMC guidelines)
      • Bastan A.
      • Cengiz M.
      • Cengiz S.
      • Polat B.
      • Colak A.
      • Akan M.
      • Darbaz I.
      • Acar D.B.
      Effects of precalving antibiotic treatment on mastitis and individual somatic cell count in heifers.
      Culturing protocol only (NMC guidelines)
      • Borm A.A.
      • Fox L.K.
      • Leslie K.E.
      • Hogan J.S.
      • Andrew S.M.
      • Moyes K.M.
      • Oliver S.P.
      • Schukken Y.H.
      • Hancock D.D.
      • Gaskins C.T.
      • Owens W.E.
      • Norman C.
      Effects of prepartum intramammary antibiotic therapy on udder health, milk production, and reproductive performance in dairy heifers.
      Culturing protocol only (NMC guidelines)
      • Bowers S.
      • Gandy S.
      • Graves K.
      • Eicher S.
      • Willard S.
      Effects of prepartum milking on postpartum reproduction, udder health and production performance in first-calf dairy heifers.
      TMAS-D-TEC test for mastitis (SCC via conductivity)
      • Bryan M.A.
      • Friton G.M.
      Stochastic economic modeling of the use of penethamate hydriodide (Mamyzin®) in heifers around calving to control peri-parturient mastitis.
      PClinical mastitis–specific signs not described
      • Bryan M.
      • Taylor K.
      Periparturient use of parenteral micronised procaine penicillin to reduce the risk of clinical mastitis in heifers after calving.
      TClinical mastitis–described signs and symptoms
      • Bush L.J.
      • Barto P.B.
      • Adams G.D.
      Effect of teat dipping on mastitis infection in dairy heifers at 1st calving.
      Culturing protocol only (NMC guidelines)
      • Compton C.W.R.
      • Emslie F.R.
      • McDougall S.
      Randomised controlled trials demonstrate efficacy of a novel internal teat sealant to prevent new intramammary infections in dairy cows and heifers.
      TCulturing protocol (NMC guidelines), >200 cfu/mL for IMI
      • Contreras G.A.
      • David Munoz J.
      • Sears P.M.
      Reducing the incidence of intramammary infection in heifers by using prepartum systemic tylosin therapy: Initial results of a single herd pilot study.
      TCulturing protocol (NMC guidelines), >500 cfu/mL for IMI
      • Edinger D.
      • Tenhagen B.A.
      • Kalbe P.
      • Klunder G.
      • Baumgartner B.
      • Heuwieser W.
      Effect of teat dipping with a germicide barrier teat dip in late gestation on intramammary infection and clinical mastitis during the first 5 days post-partum in primiparous cows.
      PCulturing protocol provided for IMI; changes in secretion and veterinary treatment for CM
      • Gentilini M.B.
      • Molina L.R.
      • Carvalho A.U.
      Use of an Escherichia coli J5 vaccine on immunization of dairy heifers against mastitis caused by E. coli..
      PCulturing protocol (NMC guidelines) for IMI; SCC >250,000 cells/mL for SCM; clinical signs for CM
      • Giraudo J.A.
      • Calzolari A.
      • Rampone H.
      • Rampone A.
      • Giraudo A.T.
      • Bogni C.
      • Larriestra A.
      • Nagel R.
      Field trials of a vaccine against bovine mastitis. 1. Evaluation in heifers.
      TPrimary pathogen cultured and SCC, >250,000 cells/mL for IMI
      • Hovareshti P.
      • Bolourchi M.
      • Tabatabayi A.H.
      Comparison of the effect of systemic and local antibacterial therapy to control staphylococcal intramammary infection in prepartum heifers.
      Culturing protocol defined for Staphylococcus aureus
      • Lopez-Benavides M.G.
      • Williamson J.H.
      • Lacy-Hulbert S.J.
      • Cursons R.T.
      Teat spraying prior to calving may reduce the risk of heifer mastitis caused by Streptococcus uberis..
      PCulturing protocol for Streptococcus uberis and CNS; clinical signs for CM
      • Lopez-Benavides M.G.
      • Cursons R.T.
      • Lacy-Hulbert S.J.
      • Williamson J.H.
      Heifer teats sprayed in the dry period with an iodine teat sanitizer have reduced Streptococcus uberis teat-end contamination and less Streptococcus uberis intra-mammary infections at calving.
      TCulturing protocol defined for S. uberis, ≥100 cfu/mL for IMI
      • Matthews K.R.
      • Harmon R.J.
      • Langlois B.E.
      • Crist W.L.
      • Hemken R.W.
      Use of latex teat dip with germicide during the prepartum period.
      TDuplicate quarter samples with same pathogen for IMI; clinical signs for CM
      • McDougall S.
      • Parker K.
      • Compton C.
      • Heuer C.
      Reducing subclinical and clinical mastitis in dairy heifers by precalving infusion of a teat sealant and/or parenteral antibiotic therapy.
      Clinical signs for CM, but signs/symptoms not described
      • McDougall S.
      • Parker K.I.
      • Weir A.M.
      • Compton C.W.R.
      Effect of application of an external teat sealant and/or oral treatment with a monensin capsule precalving on the prevalence and incidence of subclinical and clinical mastitis in dairy heifers.
      TSame pathogen isolated from sequential or parallel milk samples for IMI
      • Middleton J.R.
      • Luby C.D.
      • Steevens B.J.
      • Lakritz J.
      • Timms L.L.
      • Bader G.R.
      Effect of prepartum intramammary treatment with pirlimycin hydrochloride on prevalence of early first-lactation mastitis in dairy heifers.
      T≤2 species cultured, and same species in 2 sequential samples for IMI; SCC reported; California Mastitis Test used for SCM
      • Nickerson S.C.
      • Owens W.E.
      • Tomita G.M.
      • Widel P.W.
      Vaccinating dairy heifers with a Staphylococcus aureus bacterin reduces mastitis at calving.
      Culturing protocol only (NMC guidelines)
      • Nickerson S.C.
      • Hovingh E.P.
      • Widel P.W.
      Immunisation of dairy heifers with a Staphylococcus aureus bacterin reduces infection level and somatic cell counts at time of calving.
      Culturing protocol only
      • Oliver S.P.
      • King S.H.
      • Lewis M.J.
      • Dowlen H.H.
      Influence of prepartum antibiotic therapy on intramammary infections (IMI) in primigravid heifers during early lactation.
      TSame pathogen isolated at 2 sequential samplings
      • Oliver S.P.
      • Lewis M.J.
      • Gillespie B.E.
      • Dowlen H.H.
      Antibiotic residues and prevalence of mastitis pathogen isolation in heifers during early lactation following prepartum antibiotic therapy.
      Culturing protocol only (NMC guidelines)
      • Oliver S.P.
      • Jaenicke E.C.
      • Roberts R.K.
      • Dowlen H.H.
      • Lewis M.J.
      • Gillespie B.E.
      Prepartum antibiotic treatment of heifers: Milk production, milk quality and economic benefit.
      Culturing protocol only (NMC guidelines)
      • Oliver S.P.
      • Dowlen H.H.
      • Moorehead H.
      • Hallberg J.W.
      • Chester S.T.
      • Lamar K.C.
      • Ivey S.J.
      • Gillespie B.E.
      • Johnson D.L.
      • Lewis M.J.
      Influence of prepartum pirlimycin hydrochloride or penicillin-novobiocin therapy on mastitis in heifers during early lactation.
      TCulturing protocol (NMC guidelines), ≥100 cfu/mL for IMI
      • Oliver S.P.
      • Headrick S.I.
      • Gillespie B.E.
      • Lewis M.J.
      • Johnson D.L.
      • Lamar K.C.
      • Moorehead H.
      • Dowlen H.H.
      • Hallberg J.W.
      Intramammary infections in heifers during early lactation following intramammary infusion of pirlimycin hydrochloride or penicillin-novobiocin at the first milking after parturition.
      TCulturing protocol (NMC guidelines), ≥100 cfu/mL for IMI
      • Owens W.E.
      • Nickerson S.C.
      • Boddie R.L.
      • Tomita G.M.
      • Ray C.H.
      Prevalence of mastitis in dairy heifers and effectiveness of antibiotic therapy.
      Culturing protocol only
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougall S.
      Subclinical and clinical mastitis in heifers following the use of a teat sealant precalving.
      T≥300 cfu/mL of same species in sequential samples for IMI
      • Parker K.I.
      • Heuer C.
      • McDougall S.
      • Compton C.W.R.
      • Anniss F.M.
      Quarter-level analysis of subclinical and clinical mastitis in primiparous heifers following the use of a teat sealant or an injectable antibiotic, or both, precalving.
      T≥300 cfu/mL of same species in parallel samples for IMI
      • Passchyn P.
      • Piepers S.
      • De Vliegher S.
      Systemic prepartum treatment of end-term dairy heifers with penethamate hydriodide: Effect on udder health, milk yield, and culling until 120 days in milk.
      T≥100 cfu/mL for IMI
      • Pellegrino M.
      • Giraudo J.
      • Raspanti C.
      • Nagel R.
      • Odierno L.
      • Primo V.
      • Bogni C.
      Experimental trial in heifers vaccinated with Staphylococcus aureus avirulent mutant against bovine mastitis.
      Culturing protocol only (NMC guidelines)
      • Pellegrino M.
      • Giraudo J.
      • Raspanti C.
      • Odierno L.
      • Bogni C.
      Efficacy of immunization against bovine mastitis using a Staphylococcus aureus avirulent mutant vaccine.
      TPresented cfu from samples
      • Robertson B.G.
      • Williamson J.H.
      • Kuhn-Sherlock B.
      • Lacy-Hulbert S.J.
      • Turner S.A.
      Use of internal teat sealant in heifers reduces mastitis and may affect milk production.
      T≥500 cfu/mL for IMI; ≥100 cfu/mL and clinical signs for CM; ≥120,000 cells/mL for SCM
      • Roy J.P.
      • Du Tremblay D.
      • DesCôteaux L.
      • Messier S.
      • Scholl D.
      • Bouchard É.
      Effect of precalving intramammary treatment with pirlimycin in nulliparous Holstein heifers.
      TDifferent IMI definitions by species, very thoroughly detailed
      • Sampimon O.C.
      • de Vliegher S.
      • Barkema H.W.
      • Sol J.
      • Lam T.J.G.M.
      Effect of prepartum dry cow antibiotic treatment in dairy heifers on udder health and milk production.
      T≥100 cfu/mL for major pathogen IMI, ≥500 cfu/mL for major pathogen IMI
      • Santos J.E.P.
      • Cerri R.L.A.
      • Kirk J.H.
      • Juchem S.O.
      • Villasenor A.
      Effect of prepartum milking of primigravid cows on mammary gland health and lactation performance.
      Culturing protocol only (NMC guidelines)
      • Tenhagen B.A.
      • Edinger D.
      • Baumgartner B.
      • Kalbe P.
      • Klunder G.
      • Heuwieser W.
      Efficacy of a herd-specific vaccine against Staphylococcus aureus to prevent post-partum mastitis in dairy heifers.
      PCulturing protocol only for IMI; clinical changes in secretion for CM; reported SCC
      • Toušová R.
      • Stádník L.
      • Ducháček J.
      • Baráková M.
      Influence of vaccination against mastitis on its incidence, somatic cells amount and content of solid components in milk of primiparous dairy cows.
      PClinical mastitis, specific signs not described
      • Vargas R.T.
      • Souza F.N.
      • Brito M.A.V.P.
      • Brito J.R.F.
      • Leite M.O.
      • Fonseca L.M.
      • Sampaio I.B.M.
      • Cerqueira M.M.O.P.
      Partial budget analysis of prepartum antimicrobial therapy and Escherichia coli J5 vaccination of dairy heifers and their effect on milk production and milk quality parameters.
       T≤2 species cultured, ≥100 cfu/mL for S. aureus and Streptococcus agalactiae IMI, ≥1,000 cfu/mL for other species
      1 T = definitions were thoroughly described; P = definitions were partially described.
      2 SCM = subclinical mastitis; CM = clinical mastitis.

      Effectiveness of Treatment

      Overall Effect Size

      The overall RR of udder disease of any sort in treated compared with untreated heifers was 0.60 (95% CI: 0.47 to 0.67), demonstrating a reduction in udder diseases after calving in treated compared with untreated heifers (P < 0.0001). Effect size estimates from abstracts/proceedings tended to be slightly lower and had more variance than estimates from full-text manuscripts (P = 0.08; Figure 2), but their inclusion did not have an effect on overall effect size (RR = 0.60 for full-text manuscripts alone; RR = 0.57 for a combined meta-analysis). All further analyses were conducted on results from both full-text manuscripts and abstracts/conference proceedings without stratification.
      Figure thumbnail gr2
      Figure 2Forest plot of effect size estimates from all (n = 48) studies included in the meta-analysis assessing effectiveness of precalving therapy at improving postcalving udder health in dairy heifers. Size of boxes reflects relative size of effect estimate; diamonds represent pooled estimates within strata. CM = clinical mastitis; new IMI = IMI that was not present precalving; SCM = subclinical mastitis (defined as elevated SCC).

      Effect Size by Outcome Type

      The majority of records (n = 34) used IMI as the outcome, whereas 15 records assessed CM and 2 assessed SCM. Effect size estimates for CM tended to be lower than those for IMI (P = 0.07), but tended to be higher than those for SCM (P = 0.06; Table 4). For subsequent meta-analyses and regressions, all outcomes other than cure rate were combined through a random-effects term included for outcome type within studies to account for any within-study correlation. Risk of cure of existing IMI following precalving treatment with antimicrobials was higher than spontaneous cure with no treatment [RR = 1.63 (95% CI: 1.19 to 2.25); P = 0.003].
      Table 4Meta-regression of records included in a systematic review precalving therapies for improving udder health in primiparous dairy heifers on the outcome used to assess udder health
      Outcome typeRisk ratio
      Ratio of risk of infection in treated heifers to risk of infection in untreated controls.
      (95% CI)
      No. of recordsHeterogeneity
      Heterogeneity refers to residual heterogeneity from meta-regression model attributed to differences among studies. I2 = statistic to quantify the amount of variation due to study heterogeneity; Q = Cochrane Q statistic for significance.
      Clinical mastitis0.50 (0.39–0.64)15I
      Heterogeneity refers to residual heterogeneity from meta-regression model attributed to differences among studies. I2 = statistic to quantify the amount of variation due to study heterogeneity; Q = Cochrane Q statistic for significance.
      = 0.85
      IMI0.61 (0.51–0.74)34Q = 343.5
      Subclinical mastitis
      Subclinical mastitis defined as a heifer having an elevated SCC (measured by electrical conductivity of milk, the California mastitis test or a quantified SCC >120,000 or 250,000 cells/mL).
      0.30 (0.18–0.50)2P < 0.0001
      1 Ratio of risk of infection in treated heifers to risk of infection in untreated controls.
      2 Heterogeneity refers to residual heterogeneity from meta-regression model attributed to differences among studies. I2 = statistic to quantify the amount of variation due to study heterogeneity; Q = Cochrane Q statistic for significance.
      3 Subclinical mastitis defined as a heifer having an elevated SCC (measured by electrical conductivity of milk, the California mastitis test or a quantified SCC >120,000 or 250,000 cells/mL).

      Effect Size by Therapy Type and Pathogen Type

      A meta-regression on treatment type using CM, SCM, and IMI as outcomes resulted in a difference in effectiveness among treatment types (Table 5). Teat sealants and combination therapies were the most effective treatments (P < 0.0001), although antimicrobials, vaccines, and other treatments still reduced risk of CM, SCM, or IMI compared with untreated controls (P < 0.0001). Teat disinfection before calving did not reduce udder disease compared with untreated controls. Records not included in the meta-analysis also reported similar patterns—antimicrobials were effective at preventing CM and IMI, as well as curing existing IMI. Farms observed longitudinally had decreasing prevalence of IMI and incidence of CM around calving after incorporating precalving antimicrobial treatment into heifer management (

      Acuña, C. N., and R. E. Chertcoff. 2003. Mastitis control program on dairies with high incidence in first calving heifers: Part 2. In Proc. 42nd NMC Annu. Mtg.

      ). Other effective management strategies were the use of physical intramammary devices (
      • Nickerson S.C.
      • Boddie R.L.
      Effects of novel intramammary devices on incidence of mastitis.
      ), implementing fly control for heifers on pasture (
      • Nickerson S.C.
      • Owens W.E.
      • Boddie R.L.
      Mastitis in dairy heifers: A historical review.
      ), and earlier removal of calves after calving to prevent suckling (
      • Compton C.
      • McDougall S.
      Effect of early milking of calved heifers and selenium supplementation on incidence of clinical mastitis in dairy heifers.
      ).
      Table 5Meta-regression of records included in a systematic review of precalving treatment for improving udder health in primiparous dairy heifers on the type of treatment assessed in the study
      Intervention type
      Antimicrobial includes antibiotics as well as antiseptic compounds such as chlorhexidine. Combinations in included studies consisted of teat sealants and antimicrobials; vaccines and antimicrobials; teat sealants, vaccines and antimicrobials. Other includes insecticides, and management practices such as prepartum milking (Appendix Table A1).
      Risk ratio
      Ratio of risk of infection in treated heifers to risk of infection in untreated controls.
      (95% CI)
      No. of recordsHeterogeneity
      Residual heterogeneity from meta-regression model attributed to differences in studies. I2 = statistic to quantify the amount of variation due to study heterogeneity; Q = Cochrane Q statistic for significance.
      Antimicrobial0.58 (0.46–0.74)27
      Teat sealant0.40
      Risk ratio different (P < 0.05) from studies assessing antimicrobial effectiveness.
      (0.30–0.52)
      7I
      Ratio of risk of infection in treated heifers to risk of infection in untreated controls.
      = 0.85
      Teat dips/spray1.50
      Risk ratio different (P < 0.05) from studies assessing antimicrobial effectiveness.
      (0.74–3.1)
      3Q = 369.78
      Vaccine0.55 (0.35–0.86)12P < 0.0001
      Combination0.34 (0.25–0.45)4
      Other0.50 (0.11–1.1)4
      1 Antimicrobial includes antibiotics as well as antiseptic compounds such as chlorhexidine. Combinations in included studies consisted of teat sealants and antimicrobials; vaccines and antimicrobials; teat sealants, vaccines and antimicrobials. Other includes insecticides, and management practices such as prepartum milking (Appendix Table A1).
      2 Ratio of risk of infection in treated heifers to risk of infection in untreated controls.
      3 Residual heterogeneity from meta-regression model attributed to differences in studies. I2 = statistic to quantify the amount of variation due to study heterogeneity; Q = Cochrane Q statistic for significance.
      4 Risk ratio different (P < 0.05) from studies assessing antimicrobial effectiveness.
      Although studies differentiated culture results to varying levels of detail, pathogens were grouped into 3 categories: contagious (Staphylococcus aureus, Streptococcus agalactiae), environmental (Escherichia coli, non-agalactiae streptococci), and CNS. Subgroup analyses including meta-regression on treatment type were conducted using the 3 categories as outcomes (Table 6). Antimicrobials, teat sealants, and vaccines all presented similar reductions (RR = 0.51, 0.40, and 0.56, respectively) in contagious pathogen CM and IMI compared with untreated controls. Only 1 study reported on teat dips/sprays (
      • Edinger D.
      • Tenhagen B.A.
      • Kalbe P.
      • Klunder G.
      • Baumgartner B.
      • Heuwieser W.
      Effect of teat dipping with a germicide barrier teat dip in late gestation on intramammary infection and clinical mastitis during the first 5 days post-partum in primiparous cows.
      ) and 1 on combination therapies (
      • McDougall S.
      • Parker K.I.
      • Weir A.M.
      • Compton C.W.R.
      Effect of application of an external teat sealant and/or oral treatment with a monensin capsule precalving on the prevalence and incidence of subclinical and clinical mastitis in dairy heifers.
      ); in both studies, the 2 therapies did not change occurrence of CM or IMI compared with controls. Manuscripts not included in the pooled estimate also reported a reduced incidence of CM and IMI by contagious pathogens when heifers received precalving treatment with antimicrobials, and also when fly control was implemented for precalving heifers on pasture.
      Table 6Meta-regression of records included in a systematic review of precalving treatment for improving udder health in primiparous dairy heifers on the type of treatment assessed in the study, stratified by type of pathogen
      Pathogen and intervention type
      Contagious pathogens include Staphylococcus aureus and Streptococcus agalactiae. Environmental pathogens include Escherichia coli and non-agalactiae streptococci.
      Antimicrobial includes antibiotics as well as antiseptic compounds such as chlorhexidine. Combinations in included studies consisted of teat sealants and antimicrobials; vaccines and antimicrobials; and teat sealants, vaccines, and antimicrobials. Other includes insecticides and management practices such as prepartum milking (Appendix Table A1).
      Risk ratio
      Ratio of risk of infection in treated heifers to risk of infection in untreated controls.
      (95% CI)
      No. of recordsHeterogeneity
      Residual heterogeneity from meta-regression model attributed to differences in studies. I2 = statistic to quantify the amount of variation due to study heterogeneity; Q = Cochrane Q statistic for significance.
      Contagious
       Antimicrobial0.41 (0.34–0.77)15
       Teat sealant0.40 (0.22–0.72)4I
      Antimicrobial includes antibiotics as well as antiseptic compounds such as chlorhexidine. Combinations in included studies consisted of teat sealants and antimicrobials; vaccines and antimicrobials; and teat sealants, vaccines, and antimicrobials. Other includes insecticides and management practices such as prepartum milking (Appendix Table A1).
      = 0.29
       Teat dips/spray1.48
      Intervention type within pathogen type stratum did not have enough records for meta-analysis. Risk ratio presented was calculated from the single record within that stratum.
      (0.52–4.27)
      1Q = 39.36
       Vaccine0.56 (0.34–0.92)8P = 0.025
       Combination0.93
      Intervention type within pathogen type stratum did not have enough records for meta-analysis. Risk ratio presented was calculated from the single record within that stratum.
      (0.33–1.26)
      1
      Environmental
       Antimicrobial0.58 (0.46–0.74)18
       Teat sealant0.27
      Risk ratio was different (P < 0.05) from studies assessing antimicrobial effectiveness.
      (0.15–0.49)
      5I
      Antimicrobial includes antibiotics as well as antiseptic compounds such as chlorhexidine. Combinations in included studies consisted of teat sealants and antimicrobials; vaccines and antimicrobials; and teat sealants, vaccines, and antimicrobials. Other includes insecticides and management practices such as prepartum milking (Appendix Table A1).
      = 0.57
       Teat dips/spray0.56 (0.17–1.8)3Q = 71.77
       Vaccine0.78 (0.20–2.98)4P < 0.0001
       Combination0.25
      Risk ratio was different (P < 0.05) from studies assessing antimicrobial effectiveness.
      (0.13–0.50)
      2
      CNS
       Antimicrobial0.51 (0.35–0.76)15
       Teat sealant0.46 (0.29–0.73)4I
      Antimicrobial includes antibiotics as well as antiseptic compounds such as chlorhexidine. Combinations in included studies consisted of teat sealants and antimicrobials; vaccines and antimicrobials; and teat sealants, vaccines, and antimicrobials. Other includes insecticides and management practices such as prepartum milking (Appendix Table A1).
      = 0.89
       Teat dips/spray1.48 (0.31–7.03)2Q = 212.71
       Vaccine0.89 (0.38–2.07)4P < 0.0001
       Combination0.34
      Risk ratio was different (P < 0.05) from studies assessing antimicrobial effectiveness.
      (0.21–0.56)
      2
       Other0.80
      Intervention type within pathogen type stratum did not have enough records for meta-analysis. Risk ratio presented was calculated from the single record within that stratum.
      (0.19–3.34)
      1
      1 Contagious pathogens include Staphylococcus aureus and Streptococcus agalactiae. Environmental pathogens include Escherichia coli and non-agalactiae streptococci.
      2 Antimicrobial includes antibiotics as well as antiseptic compounds such as chlorhexidine. Combinations in included studies consisted of teat sealants and antimicrobials; vaccines and antimicrobials; and teat sealants, vaccines, and antimicrobials. Other includes insecticides and management practices such as prepartum milking (Appendix Table A1).
      3 Ratio of risk of infection in treated heifers to risk of infection in untreated controls.
      4 Residual heterogeneity from meta-regression model attributed to differences in studies. I2 = statistic to quantify the amount of variation due to study heterogeneity; Q = Cochrane Q statistic for significance.
      5 Intervention type within pathogen type stratum did not have enough records for meta-analysis. Risk ratio presented was calculated from the single record within that stratum.
      6 Risk ratio was different (P < 0.05) from studies assessing antimicrobial effectiveness.
      Teat sealants and combination therapies reduced occurrence of CM and IMI with environment pathogens over untreated controls (RR = 0.27 and 0.25, respectively; Table 6). Antimicrobials, teat disinfection, and vaccines did not have any benefit compared with untreated controls, but 2 studies not included in the meta-analysis (
      • Nickerson S.C.
      • Owens W.E.
      • Boddie R.L.
      Mastitis in dairy heifers: A historical review.
      ;
      • Tenhagen B.A.
      • Edinger D.
      • Baumgartner B.
      • Kalbe P.
      • Klunder G.
      • Heuwieser W.
      Efficacy of a herd-specific vaccine against Staphylococcus aureus to prevent post-partum mastitis in dairy heifers.
      ) reported a reduction of clinical signs during E. coli IMI following precalving vaccination. Fly control for heifers on pasture reduced Streptococcus spp. IMI. Studies reporting on CM and IMI where CNS were isolated reported a reduction compared with controls in heifers treated with antimicrobials, teat-sealants, and combination therapies, with combination therapies having the greatest reduction (RR = 0.34), and similar conclusions were drawn from studies not included in the meta-analysis. Vaccines did not reduce CM and IMI with CNS occurrence compared with untreated controls. Due to only single studies assessing other therapies and teat dips/sprays, pooling was not possible, but neither demonstrated a reduction in occurrence of CM and IMI with CNS compared with untreated controls.

      Meta-Analysis Statistics

      Heterogeneity

      Significant heterogeneity was present in all analyses. Mixed effects meta-analysis using all records with random effects for outcome type and intervention type had an overall I2 = 0.87 (Q = 439.28, P < 0.0001). Introducing outcome type as a moderator did not reduce heterogeneity noticeably; I2 = 0.85 (Q = 343.54, P < 0.0001), nor did conducting a meta-regression using outcome type affect heterogeneity; I2 = 0.85 (Q = 369.78, P < 0.0001). Sub-group analyses by pathogen type led to reductions in residual heterogeneity, except for the CNS analysis: contagious pathogen analysis I2 = 0.29 (Q = 39.36, P = 0.03); environmental pathogen analysis I2 = 0.57 (Q = 71.77, P < 0.0001); CNS analysis I2 = 0.88 (Q = 212.71, P < 0.0001).

      Publication Bias

      Based on visual assessment of the funnel plot of standard error compared with the effect size estimate (Figure 3) from each study, we inferred that some asymmetry due to missing studies showing an increased risk following treatment with small sample sizes (bottom right quadrant). Egger's regression small study effects indicated a possibility of publication bias as an increasing standard error was associated with a larger effect size estimate (P < 0.0001; Figure 4).
      Figure thumbnail gr3
      Figure 3Egger's regression for small-study effects in a meta-analysis of studies assessing effectiveness of precalving therapies at improving udder health in dairy heifers plotted as the natural log of the risk ratio from a given study against the estimate of variance from the same study. Vertical bars indicate 95% confidence intervals at the intercept (variance = 0; largest possible studies).
      Figure thumbnail gr4
      Figure 4Funnel plot to assess asymmetry and publication bias in meta-analysis of studies assessing effectiveness of precalving therapies at improving udder health in dairy heifers. Relative risk = 1 indicates equal risk of udder disease in treated and untreated animals (no effect of treatment). Darkest triangle indicates area of 90% confidence, light gray triangle indicates area of 95% confidence, and white triangle indicates area of 99% confidence.

      DISCUSSION

      Management of mastitis on dairy farms often starts after the heifer's first calving, too often resulting in less than optimal udder health for first lactation heifers (
      • De Vliegher S.
      • Fox L.K.
      • Piepers S.
      • McDougall S.
      • Barkema H.W.
      Invited review: Mastitis in dairy heifers: Nature of the disease, potential impact, prevention, and control.
      ). Many housing and management practices associated with udder health of older cows are also associated with improved udder health in primiparous heifers (
      • De Vliegher S.
      • Fox L.K.
      • Piepers S.
      • McDougall S.
      • Barkema H.W.
      Invited review: Mastitis in dairy heifers: Nature of the disease, potential impact, prevention, and control.
      ), but the level of implementation in nonlactating heifers is unknown. Prophylactic treatments of the udder before calving (e.g., antimicrobial dry cow therapy or using internal teat sealants) are widely adopted for use in the lactating herd (e.g.,
      • Olde Riekerink R.G.
      • Barkema H.W.
      • Scholl D.T.
      • Poole D.E.
      • Kelton D.F.
      Management practices associated with the bulk-milk prevalence of Staphylococcus aureus in Canadian dairy farms.
      ), but these treatments are less commonly used in primiparous heifers. This systematic review and meta-analysis of studies assessing effectiveness of precalving therapies for improving postcalving udder health in heifers demonstrated an overall benefit to udder health in heifers when using any kind of precalving prophylactic treatment. Treatments varied in both cost to purchase as well as costs and labor associated with application, so an understanding of the effectiveness of treatments is important to inform management decisions. Effectiveness of treatments varied considerably and was also dependent on the type of bacteria causing the IMI.
      This is the first review to meta-analyze results from studies of multiple types of precalving therapies in primiparous heifers. Recent reviews have considered heifer mastitis as a whole (
      • De Vliegher S.
      • Fox L.K.
      • Piepers S.
      • McDougall S.
      • Barkema H.W.
      Invited review: Mastitis in dairy heifers: Nature of the disease, potential impact, prevention, and control.
      ), antimicrobial treatment to control heifer mastitis (
      • Nickerson S.C.
      Control of heifer mastitis: Antimicrobial treatment—An overview.
      ), vaccination efficacy against staphylococcal infections in all lactating cattle (
      • Middleton J.R.
      • Luby C.D.
      • Adams D.S.
      Efficacy of vaccination against staphylococcal mastitis: A review and new data.
      ), and effectiveness of treatments other than conventional antimicrobials against CM in all lactating cows (
      • Francoz D.
      • Wellemans V.
      • Dupré J.P.
      • Roy J.-P.
      • Labelle F.
      • Lacasse P.
      • Dufour S.
      Invited review: A systematic review and qualitative analysis of treatments other than conventional antimicrobials for clinical mastitis in dairy cows.
      ). The distribution of pathogens in IMI of heifers differs from older cows (
      • Piepers S.
      • DeVliegher S.
      • DeKruif A.
      • Opsomer G.
      • Barkema H.W.
      Impact of intramammary infections in dairy heifers on future udder health, milk production, and culling.
      ;
      • Supré K.
      • Haesebrouck F.
      • Zadoks R.N.
      • Vaneechoutte M.
      • Piepers S.
      • De Vliegher S.
      Some coagulase-negative Staphylococcus species affect udder health more than others.
      ;
      • Naqvi S.A.
      • De Buck J.
      • Dufour S.
      • Barkema H.W.
      Udder health in Canadian dairy heifers during early lactation.
      ), as well as their immune response to infection (
      • de Haas Y.
      • Barkema H.W.
      • Veerkamp R.F.
      The effect of pathogen-specific clinical mastitis on the lactation curve for somatic cell count.
      ,
      • de Haas Y.
      • Veerkamp R.F.
      • Barkema H.W.
      • Gröhn Y.T.
      • Schukken Y.H.
      Associations between pathogen-specific cases of clinical mastitis and somatic cell count patterns.
      ), so results from studies on older lactating cattle may not be generalizable to heifers. A synthesis of studies aimed at heifers in particular is therefore necessary when trying to implement more targeted management strategies. Findings from this review were in line with most individual studies and reviews on lactating cows that demonstrated a net positive benefit of any type of treatment for improving udder health. Previous reviews have demonstrated differential effectiveness of antimicrobials (
      • Barkema H.W.
      • Schukken Y.H.
      • Zadoks R.N.
      Invited review: The role of cow, pathogen, and treatment regimen in the therapeutic success of bovine Staphylococcus aureus mastitis.
      ;
      • Nickerson S.C.
      Control of heifer mastitis: Antimicrobial treatment—An overview.
      ) and teat sealants (
      • Crispie F.
      • Flynn J.
      • Ross R.P.
      • Hill C.
      • Meaney W.J.
      Dry cow therapy with a non-antibiotic intramammary teat seal–A review.
      ), based on the pathogen (when used in lactating cows), whereas vaccine development tends to focus on a specific type of pathogen such as S. aureus (
      • Middleton J.R.
      • Luby C.D.
      • Adams D.S.
      Efficacy of vaccination against staphylococcal mastitis: A review and new data.
      ) or E. coli (Enviracor and StartVac). Compared with the present review focusing on heifers specifically, variation in treatment effectiveness by pathogen type was similar to previous reports from studies focusing on older cows.
      As mentioned above, management of nonlactating heifers is less than ideal, with practices such as comingling with older cattle and moving cows close to calving and increasing stress being common on most dairy farms (
      • Parker K.I.
      • Compton C.
      • Anniss F.
      • McDougall S.
      Management of dairy heifers and its relationships with the incidence of clinical mastitis.
      ;
      • McDougall S.
      • Parker K.I.
      • Heuer C.
      • Compton C.W.R.
      A review of prevention and control of heifer mastitis via non-antibiotic strategies.
      ). This could be an important reason why treatments were effective in improving udder health. It is therefore likely that effectiveness of treatments, particularly antimicrobial treatment, will be less on farms that devote more attention to nonlactating heifers.
      Although the effectiveness of antimicrobials was consistent across gram-positive pathogens, their use needs to be balanced with concerns about the rising prevalence of antimicrobial resistance (
      • Barkema H.W.
      • von Keyserlingk M.A.G.
      • Kastelic J.P.
      • Lam T.J.G.M.
      • Luby C.
      • Roy J.-P.
      • LeBlanc S.J.
      • Keefe G.P.
      • Kelton D.F.
      Invited review: Changes in the dairy industry affecting dairy cattle health and welfare.
      ;
      • Tang K.L.
      • Caffrey N.P.
      • Nóbrega D.B.
      • Cork S.C.
      • Ronksley P.E.
      • Barkema H.W.
      • Polachek A.J.
      • Ganshorn H.
      • Sharma N.
      • Kellner J.D.
      • Ghali W.A.
      Restricting the use of antibiotics in food-producing animals and its associations with antibiotic resistance in food-producing animals and human beings: A systematic review and meta-analysis.
      ). To prevent overuse, the NMC's 10-point plan for heifer mastitis management recommends prepartum antibiotic treatment only under very specific conditions. Other treatments can be just as effective, if not more so, than antimicrobials in heifers, and current research is beginning to focus on their effectiveness in older cows (
      • Francoz D.
      • Wellemans V.
      • Dupré J.P.
      • Roy J.-P.
      • Labelle F.
      • Lacasse P.
      • Dufour S.
      Invited review: A systematic review and qualitative analysis of treatments other than conventional antimicrobials for clinical mastitis in dairy cows.
      ;
      • Ruiz R.
      • Tedeschi L.O.
      • Sepúlveda A.
      Investigation of the effect of pegbovigrastim on some periparturient immune disorders and performance in Mexican dairy herds.
      ). Antimicrobial treatment of nonlactating heifers improved udder health more than other treatments when contagious (gram-positive) bacteria caused udder health problems after calving. In contrast, teat sealants and combination therapies were more effective than antimicrobial treatment when environmental pathogens were involved, suggesting that antimicrobials are not always the best option. It is therefore important when udder health problems after calving are an issue on a farm and antimicrobial treatment is considered, to culture quarter milk of heifers after calving.
      In addition to selecting the best treatment for each farm, personnel must also be properly trained in its application. For example, improper application of intramammary treatments, either causing trauma by inserting the cannula too far or using poor hygiene, can actually increase a quarter's risk of infection (
      • du Preez J.H.
      Bovine mastitis therapy and why it fails.
      ). It is difficult to quantify the effect of iatrogenic infections in studies included in this review. Although some studies mentioned disinfection/preparatory procedures, no studies detailed training for personnel in treatment application. Safety of treatment application and ease of application may also vary by treatment type and should be considered when selecting a treatment. For example, feed supplements are much easier and safer to administer compared with prepartum intramammary infusions of antimicrobials. A comparison of systemic antibiotic treatment with those applied intramammarily could further inform decisions if they differ in effectiveness or ease of application. This comparison was not possible for the present review because intramammary infusions of antibiotics (n = 31) greatly outnumbered systemically applied antimicrobials (n = 6), resulting in a lack of power due to the unbalanced groups. Similarly, a comparison of antimicrobial treatments based on classes may have resulted in differences in effectiveness; however, because the vast majority of antibiotic products used in the included studies were macrolides or macrolide combinations, lack of power was again an issue.
      • Nickerson S.C.
      Control of heifer mastitis: Antimicrobial treatment—An overview.
      provided a more comprehensive and in-depth review specific to antimicrobial treatments for heifers.
      In comparing all types of treatments for heifers, this review faced the challenge of significant between-study variability, not only in treatments used, but also in other aspects of study design and setting. Although we tried to explore heterogeneity through subgroup analyses, many other study characteristics still varied considerably to allow for valid subgroup analyses (e.g., timing of treatment application, study location, timing of data collection, and geographic location). As a result, significant residual heterogeneity was present even after stratification. Although the significant between-study variability may cast some doubt on the precision of the pooled results, the overall message remains unchanged, as the direction of the effect remained consistent among studies, even if the effect size did not. Specifically, precalving treatment of heifers improved udder health after calving, and the degree of improvement varied by treatment type and pathogen. Variation in characteristics such as breed, geographic location, and sampling season or timing of treatment application and specific treatment are inherently linked, making it difficult to be consistent across studies from various countries and studying a variety of treatments.
      An assessment of the risk of bias focuses on characteristics of study design and reporting in a way that is less dependent on factors outside of the researchers' control. The assessment using the SYRCLE tool (
      • Hooijmans C.R.
      • Rovers M.M.
      • De Vries R.B.
      • Leenaars M.
      • Ritskes-Hoitinga M.
      • Langendam M.W.
      SYRCLE's risk of bias tool for animal studies.
      ) highlighted some areas with significant risk of bias. Although randomization of housing and outcome assessment order are less likely to contribute to detection or performance bias in livestock studies (SYRCLE was designed for laboratory trials using animals), blinding of both treatment allocator or outcome assessor was not mentioned in most of the studies, nor was allocation concealment. For some outcomes (e.g., SCM or IMI), blinding may be inherent, because milk samples are collected by farm personnel and the outcome (SCC or bacterial culture) is assessed by laboratory technicians. Despite the possible inherent blinding of outcome assessors, lack of blinding of the treatment allocator could still contribute to detection bias, and both types of blinding should be reported, with justification provided if blinding was not done. Similarly, randomization and allocation sequence generation were only described in 6 studies, and presented a possible source of selection bias. Clear outcome definitions, especially for IMI, were also inconsistently reported; therefore, different definitions could contribute to residual heterogeneity. Although just defining IMI did not change effect size from studies that did not, looking at specific definitions would likely provide different results because each would have its own operating characteristics (
      • Dohoo I.
      • Andersen S.
      • Dingwell R.
      • Hand K.
      • Kelton D.
      • Leslie K.
      • Schukken Y.
      • Godden S.
      Diagnosing intramammary infections: Comparison of multiple versus single quarter milk samples for the identification of intramammary infections in lactating dairy cows.
      ,
      • Dohoo I.R.
      • Smith J.
      • Andersen S.
      • Kelton D.F.
      • Godden S.
      Diagnosing intramammary infections: Evaluation of definitions based on a single milk sample.
      ). This likely is not a reflection of study quality, but more on inconsistency in reporting standards for studies on livestock. The Reporting Guidelines for Randomized Controlled Trials for Livestock (REFLECT;
      • O'Connor A.M.
      • Sargeant J.M.
      • Gardner I.A.
      • Dickson J.S.
      • Torrence M.E.
      • Dewey C.E.
      • Dohoo I.R.
      • Evans R.B.
      • Gray J.T.
      • Greiner M.
      • Keefe G.
      • Lefebvre S.L.
      • Morley P.S.
      • Ramirez A.
      • Sischo W.
      • Smith D.R.
      • Snedeker K.
      • Sofos J.
      • Ward M.P.
      • Wills R.
      The REFLECT statement: Methods and processes of creating reporting guidelines for randomized controlled trials for livestock and food safety.
      ) were developed to address this issue, but are still not widely implemented. Although this review reports on a substantial number of studies, an updated review in the future once the REFLECT statement is more widely implemented would likely detect more consistency among studies, leading to more precise pooled estimates of protective effect size.
      As the first review to focus on the effectiveness of all existing precalving therapies at improving udder health in primiparous dairy heifers, the present study effectively synthesized results from a large number of studies. Heterogeneity was explored through subgroup analyses and meta-regression, focusing primarily on the main goals of the study: understanding variation in therapy success by treatment type and pathogen. Despite this exploration of heterogeneity, even stratification by both treatment type and pathogen still yielded significant residuals and unexplained study variability. As discussed, this was likely a reflection of differences in study settings, design characteristics, and reporting. Although this degree of study variability affected precision of pooled estimates, based on the direction of the effect, there was a positive effect on udder health when precalving treatments were applied. Publication bias in a review is another aspect that could affect the reliability of findings, and Egger's regression indicated that there were significant small-study effects in the review. Based on examination of the funnel plot, no studies had a negative effect of precalving treatment and used a small sample size. Although this may be a reflection of publication bias, in this case it is more clearly reflective of the true heterogeneity in the included studies, attributed primarily to treatment intensity and differences in underlying risk (
      ). Treatments varied considerably in timing of application and dosage, both of which would increase variability. Differences in geographical location, affecting housing, nutrition and other management factors, and animal breed could have contributed to differences in regional risks for mastitis, or differences in susceptibilities of heifers to disease. Asymmetry in the funnel plot may also be an artifact (
      ), as the majority of interventions under study were very unlikely to increase the risk of udder diseases over untreated heifers, making it very unlikely that small studies would show harm to udder health by precalving treatments. Although statistical evidence suggested publication bias, this was more likely a reflection of study variability as quantified by the residual heterogeneity rather than a bias in study selection.

      CONCLUSIONS

      In this first review of precalving treatments for improving udder health in primiparous dairy heifers, we assessed the findings of 60 studies, 48 of which were meta-analyzed for pooled estimates. Overall, any type of precalving therapy improved udder health by reducing occurrence of IMI, CM, and SCM compared with untreated controls. Variation in success by therapy type demonstrated that studies assessing antimicrobials, teat sealants, vaccines, and combination therapies demonstrated a significant reduction in the risk of udder disease, whereas those using teat dips/sprays or other types of therapy did not reduce risk compared with untreated heifers. There was also significant variation by pathogens that the studies examined: antimicrobials, teat sealants, vaccines, and combination therapies were effective at reducing risk of udder disease caused by contagious pathogens; antimicrobials, teat sealants, and vaccines were effective at reducing risk of udder disease caused by environmental pathogens; and finally, antimicrobials, teat sealants, vaccines, and combinations were effective at reducing udder disease caused by CNS. Once rigid reporting guidelines are more widely implemented by journals and authors, an updated literature review on udder health of dairy heifers should yield more precise pooled estimates, with decreased between-study variability.

      ACKNOWLEDGMENTS

      This study was supported by the Industrial Research Chair in Infectious Diseases of Dairy Cattle, funded by Canada's Natural Sciences and Engineering Research Council (NSERC) Industrial Research Chair Program (Ottawa, ON, Canada), with industry contributions from Alberta Milk (Edmonton, AB, Canada), the Dairy Farmers of Canada (Ottawa, ON, Canada), Westgen Endowment Fund (Milner, BC, Canada), the BC Dairy Association (Burnaby, BC, Canada), Canadian Dairy Network (Guelph, ON, Canada), CanWest DHI (Guelph, ON, Canada), and Dairy Farmers of Manitoba (Winnipeg, MN, Canada). The first and second authors were supported by a NSERC CREATE in Milk Quality Graduate student scholarship from the Canadian Bovine Mastitis and Milk Quality Research Network (Saint-Hyacinthe, QC). The first author was also supported by a Queen Elizabeth II scholarship from the province of Alberta. We also thank Todd Wilson and Karen Tang (teaching assistants for MDCH 741: Systematic Reviews and Meta-Analysis at the University of Calgary) for their help in planning the review and refining research questions, Lorraine Toews (librarian at the Health Sciences Library at the University of Calgary) for her assistance in developing the database and gray literature search strategies, and John Kastelic (University of Calgary) for editing the manuscript.

      APPENDIX

      The following search terms were used in database searches. The MeSH search is integrated in the Web of Science, so the same terms were employed there.
      The search terms used were separated into 3 separate components corresponding to the study population, intervention, and outcome type. Each of these was combined with the Boolean operator AND. Subject heading searches were conducted separately from the text search as the available subject headings were not comprehensive.
      • 1)
        To identify studies with a study population looking at heifers and not just all cows grouped together, the search was split into 2 parts (to ensure that the age of animals in the study was appropriate, as well as restrict our search to dairy cows only), which were combined using the Boolean operator AND:
        • a.
          The terms “dairy” and “milk*” combined with the Boolean operator OR. The corresponding subject headings were “dairy herds,” “dairy cows,” “dairy cattle,” and “milking” combined with the operator OR.
        • b.
          The terms “heifer*,” “primiparous,” “primigravid,” “nulliparous” combined with the Boolean operator OR. The corresponding subject headings were “heifers” and “bred heifers” combined with the Boolean operator OR.
      • 2)
        To identify studies with the relevant interventions, the search was again split into 2 parts (timing of intervention had to be precalving, as well as specify all types of intervention), which were again combined using the Boolean operator AND:
        • a.
          The terms “precalving,” “prepartum,” and “calving” combined with the Boolean operator OR. The corresponding subject heading search terms were “calving” and “prepartum period” combined using the operator OR.
        • b.
          The terms “therap*,” “treat*,” “antimicrob*,” “antibiotic,” and “seal*” combined using the operator OR. The corresponding subject headings were “drug therapy,” “therapy,” “treatment,” and “combination therapy” combined using the Boolean operator OR.
      • 3)
        To identify all possibly relevant outcomes the search terms used were “mastit*,” “infect*,” “clinical mastit*,” “bacteri*,” “inflam*,” “pathogen,” and “microorganism” combined using the Boolean operator OR. The corresponding subject headings used were “mastitis,” “summer mastitis,” “subclinical mastitis,” “mycotic mastitis,” “bovine mastitis,” and “inflammation” combined using the Boolean operator OR.
      Table A1Details on product used, primary therapeutic ingredient(s), method of application, and categorization of intervention for each of the 62 studies
      AM = antimicrobial; TSE = teat sealant; TD = teat dips/sprays; VAC = vaccine; COM = combination of multiple types.
      ReferenceProduct(s) used (intervention category)

      Acuña, C. N., and R. E. Chertcoff. 2003. Mastitis control program on dairies with high incidence in first calving heifers: Part 2. In Proc. 42nd NMC Annu. Mtg.

      Intramammary cloxacillin benzathine (AM)
      • Acuña C.N.
      • Casasnovas G.F.
      • Terminiello S.
      • Moreno A.
      • Santarcangelo C.G.
      • Simon L.O.
      Use of dry cow therapy with internal teat sealant for the prevention of clinical mastitis occurring after calving in heifers with Staphylococcus aureus.
      Enemast dry cow (Merial Argentina), intramammary cloxacillin benzathine and ampicillin trihydrate (AM)
      Acuña Pasqualina et al. (2006)Dry-off (WestfaliaSurge Argentina), external teat sealant (TSE)
      • Alaniz G.R.
      • Meinert T.R.
      • Loveland W.J.
      • Gallo G.
      • Salmon S.A.
      Evaluation of Escherichia coli bacterin, J-5 strain, as an aid in the control of clinical signs associated with E. coli mastitis in dairy cows.
      Enviracor J-5 (Pfizer Animal Health), Escherichia coli vaccine (VAC)
      • Ataee O.
      • Hovareshti P.
      • Bolourchi M.
      • Barin A.
      • Gerami A.
      • Niasari-Naslaji A.
      Effect of systemic antibacterial administration during prepartum period on coagulase negative staphylococcal intramammary infection in Holstein heifers.
      Tyloject (Razak Co., Tehran, Iran), intramuscular tylosin (AM)
      Cefquinome (Cobactan; Intervet, Boxmeer, the Netherlands), intramuscular cefquinome (AM)
      • Barto P.B.
      • Bush L.J.
      Effect of prepartum antibiotic infusion on mastitis infection in dairy cows at first calving.
      Benzathine cephapirin (Bristol Laboratories, Syracuse, NY), intramammary (AM)
      • Bassel L.
      • Kelton D.
      • Godkin A.
      • Leslie K.
      • Lissemore K.
      Risk factors for intramammary infection at first calving in heifers from Ontario sentinel herds.
      Observational study, comparison of farms using and not using precalving teat dipping (TD)
      • Bastan A.
      • Cengiz M.
      • Cengiz S.
      • Polat B.
      • Colak A.
      • Akan M.
      • Darbaz I.
      • Acar D.B.
      Effects of precalving antibiotic treatment on mastitis and individual somatic cell count in heifers.
      Rilexine 500 (Virbac, France), intramammary cephalexin monohydrate and neomycin (AM)
      • Borm A.A.
      • Fox L.K.
      • Leslie K.E.
      • Hogan J.S.
      • Andrew S.M.
      • Moyes K.M.
      • Oliver S.P.
      • Schukken Y.H.
      • Hancock D.D.
      • Gaskins C.T.
      • Owens W.E.
      • Norman C.
      Effects of prepartum intramammary antibiotic therapy on udder health, milk production, and reproductive performance in dairy heifers.
      Cefa-Lak (Fort Dodge Animal Health, Fort Dodge, IA), intramammary cephapirin sodium (AM)
      • Bowers S.
      • Gandy S.
      • Graves K.
      • Eicher S.
      • Willard S.
      Effects of prepartum milking on postpartum reproduction, udder health and production performance in first-calf dairy heifers.
      Prepartum milking twice daily beginning 3 wk prepartum (other)
      • Bray D.R.
      • Elvinger F.
      • de la Sota R.L.
      • Natzke R.P.
      • Reed P.A.
      • Shearer J.K.
      Prevalence of infection in mammary quarters of nulliparous heifers and efficacy of intra-mammary infusion of antibiotics three weeks before parturition.
      Intramammary penicillin and dihydrostreptomycin (AM)
      • Bryan M.A.
      • Friton G.M.
      Stochastic economic modeling of the use of penethamate hydriodide (Mamyzin®) in heifers around calving to control peri-parturient mastitis.
      Masticillin (Stockguard Laboratories Ltd., Hamilton, New Zealand), intramuscular procaine penicillin (AM)
      • Bryan M.
      • Taylor K.
      Periparturient use of parenteral micronised procaine penicillin to reduce the risk of clinical mastitis in heifers after calving.
      Mamyzin (Boehringer Ingelheim Vetmedica GmbH), parenteral penethemate hydroiodide (AM)
      • Bush L.J.
      • Barto P.B.
      • Adams G.D.
      Effect of teat dipping on mastitis infection in dairy heifers at 1st calving.
      Iodine teat dip (TD)
      • Compton C.
      • McDougall S.
      Effect of early milking of calved heifers and selenium supplementation on incidence of clinical mastitis in dairy heifers.
      Intercept (Bayer, New Zealand Ltd., Manukau City, New Zealand), bismuth subnitrate and chlorhexidine internal teat sealant (COM)
      • Compton C.W.R.
      • Emslie F.R.
      • McDougall S.
      Randomised controlled trials demonstrate efficacy of a novel internal teat sealant to prevent new intramammary infections in dairy cows and heifers.
      Reducing interval from calving to first milking (other);
      SelPor (Ancare, New Zealand), precalving, pour-on selenium feed supplementation (other)
      • Contreras G.A.
      • David Munoz J.
      • Sears P.M.
      Reducing the incidence of intramammary infection in heifers by using prepartum systemic tylosin therapy: Initial results of a single herd pilot study.
      Tylosin (Elanco, Greenfield, IN), intramuscular (AM)
      • Edinger D.
      • Tenhagen B.A.
      • Kalbe P.
      • Klunder G.
      • Baumgartner B.
      • Heuwieser W.
      Effect of teat dipping with a germicide barrier teat dip in late gestation on intramammary infection and clinical mastitis during the first 5 days post-partum in primiparous cows.
      Gelstadip (Pfizer GmbH, Karlsruhe, Germany), iodine teat dip (TD)
      • Galphin S.P.
      • Patrick E.
      Evaluation of insecticide impregnated tail tags for preventing intramammary infection in dairy heifers.
      Insecticide impregnated tail tag (other)
      • Gentilini M.B.
      • Molina L.R.
      • Carvalho A.U.
      Use of an Escherichia coli J5 vaccine on immunization of dairy heifers against mastitis caused by E. coli..
      Rotatec–J5 E. coli vaccine (VAC)
      • Gilbert D.
      Use of internal teat sealants in pre calving heifers to control early lactational mastitis in UK.
      Orbeseal (Zoetis Animal Health), internal teat sealant (TSE)
      • Giraudo J.A.
      • Calzolari A.
      • Rampone H.
      • Rampone A.
      • Giraudo A.T.
      • Bogni C.
      • Larriestra A.
      • Nagel R.
      Field trials of a vaccine against bovine mastitis. 1. Evaluation in heifers.
      Proprietary Staphylococcus aureus vaccine (VAC)
      • Han H.R.
      • Park H.M.
      A field trial with a bovine staphylococcal mastitis vaccine in lactating cows and heifers.
      Proprietary S. aureus vaccine (VAC)
      • Hovareshti P.
      • Bolourchi M.
      • Tabatabayi A.H.
      Comparison of the effect of systemic and local antibacterial therapy to control staphylococcal intramammary infection in prepartum heifers.
      Nafpenzal DC (Intervet International, Holland), intramammary sodium naficillin, procaine benzyl penicillin and dihydrostreptomycin (AM);
      Tylan (Elanco Animal Health, Eli Lilly), intramammary tylosin (AM);
      Baytril (Bayer, Bayer Leverkusen, Germany), subcutaneous enrofloxacin (AM)
      • Jimenez L.
      • Timon R.
      • Marco J.
      Effect of Cefalonium on intramammary infections and on milk production of heifers before their first calving.
      Cepravin VS–intramammary cephalonium (AM)
      • Lopez-Benavides M.G.
      • Cursons R.T.
      • Lacy-Hulbert S.J.
      • Williamson J.H.
      Heifer teats sprayed in the dry period with an iodine teat sanitizer have reduced Streptococcus uberis teat-end contamination and less Streptococcus uberis intra-mammary infections at calving.
      Teatguard Plus (Ecolab, Hamilton, New Zealand), iodine teat spray (TD)
      • Lopez-Benavides M.G.
      • Williamson J.H.
      • Lacy-Hulbert S.J.
      • Cursons R.T.
      Teat spraying prior to calving may reduce the risk of heifer mastitis caused by Streptococcus uberis..
      Teatguard Plus (Ecolab), iodine teat spray (TD)
      • Matthews K.R.
      • Harmon R.J.
      • Langlois B.E.
      • Crist W.L.
      • Hemken R.W.
      Use of latex teat dip with germicide during the prepartum period.
      Latex external teat sealant with germicide (TSE)
      • McCarthy K.K.
      • Kreft R.
      • Sears P.M.
      Effect of prepartum intramammary treatment in heifers on postpartum intramammary infections, somatic cell count and milk production.
      Albadry Plus (Pfizer Inc.), intramammary novobiocin, penicillin G (AM);
      Orbeseal (Pfizer Inc.), internal teat sealant (TSE);
      T-Hexx (Hydromer), teat dip (TD)
      • McDougall S.
      • Parker K.
      • Compton C.
      • Heuer C.
      Reducing subclinical and clinical mastitis in dairy heifers by precalving infusion of a teat sealant and/or parenteral antibiotic therapy.
      Teatseal (Pfizer Animal Health, Auckland, New Zealand), bismuth subnitrate internal teat sealant (TSE);
      Tylan 200 (Elanco Animal Health, Manukau City, New Zealand), intramuscular tylosin (AM)
      • McDougall S.
      • Parker K.I.
      • Weir A.M.
      • Compton C.W.R.
      Effect of application of an external teat sealant and/or oral treatment with a monensin capsule precalving on the prevalence and incidence of subclinical and clinical mastitis in dairy heifers.
      DryFlex (DeLaval, Hamilton, New Zealand), external teat sealant (TSE);
      Rumensin ABC (Elanco Animal Health, Manuaku City, New Zealand), parenteral monensin (AM)
      • Middleton J.R.
      • Luby C.D.
      • Steevens B.J.
      • Lakritz J.
      • Timms L.L.
      • Bader G.R.
      Effect of prepartum intramammary treatment with pirlimycin hydrochloride on prevalence of early first-lactation mastitis in dairy heifers.
      Pirsue (Pfizer Inc., Kalamazoo MI), intramammary pirlimycin hydrochloride (AM)
      • Newton H.
      • Chambers G.
      Incidence of peri-calving clinical mastitis in maiden heifers treated with an internal teat sealant at varying precalving intervals.
      Teat Seal (Zoetis), internal teat sealant (TSE)
      • Nickerson S.C.
      • Boddie R.L.
      Effects of novel intramammary devices on incidence of mastitis.
      5 intramammary device models (other)
      • Nickerson S.C.
      • Owens W.E.
      • Boddie R.L.
      Mastitis in dairy heifers: A historical review.
      Fly control (other); dry cow antibiotic (AM)
      • Nickerson S.C.
      • Owens W.E.
      • Tomita G.M.
      • Widel P.W.
      Vaccinating dairy heifers with a Staphylococcus aureus bacterin reduces mastitis at calving.
      Lysigin (Boehringer Ingelheim Vetmedica Inc., St. Joseph, MO), S. aureus vaccine (VAC)
      • Nickerson S.C.
      • Hovingh E.P.
      • Widel P.W.
      Immunisation of dairy heifers with a Staphylococcus aureus bacterin reduces infection level and somatic cell counts at time of calving.
      Lysigin (Boehringer Ingelheim Vetmedica Inc.), S. aureus vaccine (VAC)
      • Norman C.B.
      • Owens W.E.
      • Boddie R.L.
      • Ray C.H.
      Efficacy of prepartum, intramammary lactating cow antibiotics in dairy heifers.
      Today (Bristol Meyers, Evansville, IN), intramammary cephapirin sodium (AM);
      Cefalak, intramammary cephapirin sodium (AM)
      • Oliver S.P.
      • King S.H.
      • Lewis M.J.
      • Dowlen H.H.
      Influence of prepartum antibiotic therapy on intramammary infections (IMI) in primigravid heifers during early lactation.
      Intramammary sodium cloxacillin; intramammary cephapirin sodium (AM)
      • Oliver S.P.
      • Lewis M.J.
      • Gillespie B.E.
      • Dowlen H.H.
      Antibiotic residues and prevalence of mastitis pathogen isolation in heifers during early lactation following prepartum antibiotic therapy.
      Today (Bristol Meyers), intramammary cephapirin sodium (AM)
      • Oliver S.P.
      • Lewis M.J.
      • Gillespie B.E.
      • Dowlen H.H.
      Influence of prepartum antibiotic administration on intramammary infections in multiparous dairy cows during early lactation.
      Pirsue (Upjohn Co., Kalamazoo, MI), intramammary pirlimycin hydrochloride (AM);
      Albacillin (Upjohn Ltd., West Sussex, England), intramammary penicillin procaine and novobiocin sodium (AM)
      • Oliver S.P.
      • Jaenicke E.C.
      • Roberts R.K.
      • Dowlen H.H.
      • Lewis M.J.
      • Gillespie B.E.
      Prepartum antibiotic treatment of heifers: Milk production, milk quality and economic benefit.
      Intramammary sodium cloxacillin (AM); intramammary cephapirin sodium (AM)
      • Oliver S.P.
      • Dowlen H.H.
      • Moorehead H.
      • Hallberg J.W.
      • Chester S.T.
      • Lamar K.C.
      • Ivey S.J.
      • Gillespie B.E.
      • Johnson D.L.
      • Lewis M.J.
      Influence of prepartum pirlimycin hydrochloride or penicillin-novobiocin therapy on mastitis in heifers during early lactation.
      Albacillin (Pfizer Animal Health, Kalamazoo, MI), intramammary novobiocin sodium and penicillin procaine (AM);
      Pirsue (Pfizer Inc.), intramammary pirlimycin hydrochloride (AM)
      • Oliver S.P.
      • Headrick S.I.
      • Gillespie B.E.
      • Lewis M.J.
      • Johnson D.L.
      • Lamar K.C.
      • Moorehead H.
      • Dowlen H.H.
      • Hallberg J.W.
      Intramammary infections in heifers during early lactation following intramammary infusion of pirlimycin hydrochloride or penicillin-novobiocin at the first milking after parturition.
      Albacillin (Pfizer Animal Health), intramammary novobiocin sodium and penicillin procaine (AM);
      Pirsue (Pfizer Inc.), intramammary pirlimycin hydrochloride (AM)
      • Owens W.E.
      • Nickerson S.C.
      • Boddie R.L.
      • Tomita G.M.
      • Ray C.H.
      Prevalence of mastitis in dairy heifers and effectiveness of antibiotic therapy.
      Tomorrow (Fort Dodge Animal Health), intramammary cephapirin benzathine (AM);
      Quartermaster (Pharmacia Upjohn, Kalamazoo, MI), intramammary penicillin and streptomycin (AM);
      Albadry Plus (Pharmacia Upjohn), intramammary penicillin and novobiocin (AM);
      Micotil (Eli Lilly and Co., Indianapolis, IN), intramammary tilmicosin (AM)
      Cefasafe (Intervet, Boxmeer, the Netherlands), intramammary cephalonium (AM)
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougall S.
      Subclinical and clinical mastitis in heifers following the use of a teat sealant precalving.
      Teat Seal (Pfizer Animal Health, New Zealand Ltd., Auckland, New Zealand), internal bismuth subnitrate teat sealant (TSE)
      • Parker K.I.
      • Heuer C.
      • McDougall S.
      • Compton C.W.R.
      • Anniss F.M.
      Quarter-level analysis of subclinical and clinical mastitis in primiparous heifers following the use of a teat sealant or an injectable antibiotic, or both, precalving.
      Teat Seal (Pfizer Animal Health, New Zealand Ltd.), internal bismuth subnitrate teat sealant (TSE)
      Tylan 200 (Elanco Animal Health, Manukau City, New Zealand), intramammary tylosin (AM)
      • Passchyn P.
      • Piepers S.
      • De Vliegher S.
      Systemic prepartum treatment of end-term dairy heifers with penethamate hydriodide: Effect on udder health, milk yield, and culling until 120 days in milk.
      Mamyzin Stop M (Boehringer Ingelheim GmbH, Ingelheim, Germany), intramuscular penethamate hydroiodide (AM)
      • Pellegrino M.
      • Giraudo J.
      • Raspanti C.
      • Nagel R.
      • Odierno L.
      • Primo V.
      • Bogni C.
      Experimental trial in heifers vaccinated with Staphylococcus aureus avirulent mutant against bovine mastitis.
      Proprietary S. aureus vaccine (VAC)
      • Pellegrino M.
      • Giraudo J.
      • Raspanti C.
      • Odierno L.
      • Bogni C.
      Efficacy of immunization against bovine mastitis using a Staphylococcus aureus avirulent mutant vaccine.
      Proprietary S. aureus vaccine (VAC)
      • Pol M.
      • Ebinger M.
      • Castelletti A.
      Efficacy of precalving treatment with parenteral danofloxacin in heifers.
      Advocin 180 (Zoetis), parenteral danofloxacin (AM)
      • Robertson B.G.
      • Williamson J.H.
      • Kuhn-Sherlock B.
      • Lacy-Hulbert S.J.
      • Turner S.A.
      Use of internal teat sealant in heifers reduces mastitis and may affect milk production.
      TeatSeal (Zoetis, Auckland, New Zealand), internal teat sealant (TSE)
      • Roger N.
      • Jiménez L.M.
      Case study: Udder health in heifers after vaccination against mastitis.
      StartVac, E. coli and S. aureus vaccine (VAC)
      • Roy J.P.
      • Du Tremblay D.
      • DesCôteaux L.
      • Messier S.
      • Scholl D.
      • Bouchard É.
      Effect of precalving intramammary treatment with pirlimycin in nulliparous Holstein heifers.
      Pirsue (Pfizer Animal Health, Kirkland, QC, Canada), intramammary pirlimycin hydrochloride (AM)
      • Sampimon O.C.
      • de Vliegher S.
      • Barkema H.W.
      • Sol J.
      • Lam T.J.G.M.
      Effect of prepartum dry cow antibiotic treatment in dairy heifers on udder health and milk production.
      Orbenin Extra Dry Cow (Pfizer, Capelle aan de IJssel, the Netherlands), intramammary cloxacillin (AM)
      • Santos J.E.P.
      • Cerri R.L.A.
      • Kirk J.H.
      • Juchem S.O.
      • Villasenor A.
      Effect of prepartum milking of primigravid cows on mammary gland health and lactation performance.
      Prepartum milking (other)
      • Tenhagen B.A.
      • Edinger D.
      • Baumgartner B.
      • Kalbe P.
      • Klunder G.
      • Heuwieser W.
      Efficacy of a herd-specific vaccine against Staphylococcus aureus to prevent post-partum mastitis in dairy heifers.
      Proprietary S. aureus vaccine (VAC)
      • Timms L.L.
      • Steffens A.
      • Allen L.
      Field trial evaluation of a persistent barrier teat dip for preventing mastitis during the dry period.
      Persistent barrier teat dip (TD)
      • Toušová R.
      • Stádník L.
      • Ducháček J.
      • Baráková M.
      Influence of vaccination against mastitis on its incidence, somatic cells amount and content of solid components in milk of primiparous dairy cows.
      StartVac, E. coli and S. aureus vaccine (VAC)
      • Trinidad P.
      • Nickerson S.C.
      Prevalence and treatment of intramammary infections in breeding age and in pregnant dairy heifers.
      Intramammary penicillin and streptomycin (AM)
      • Trinidad P.
      • Nickerson S.C.
      • Alley T.K.
      • Adkinson R.W.
      Efficacy of intramammary treatment in unbred and primigravid dairy heifers.
      Intramammary penicillin and streptomycin (AM)
      • Vargas R.T.
      • Souza F.N.
      • Brito M.A.V.P.
      • Brito J.R.F.
      • Leite M.O.
      • Fonseca L.M.
      • Sampaio I.B.M.
      • Cerqueira M.M.O.P.
      Partial budget analysis of prepartum antimicrobial therapy and Escherichia coli J5 vaccination of dairy heifers and their effect on milk production and milk quality parameters.
      Albadry Plus (Pfizer Animal Health), novobiocin sodium and procaine penicillin (AM);
      Enviracor J5 (Pfizer Animal Health), E. coli vaccine (VAC)
      1 AM = antimicrobial; TSE = teat sealant; TD = teat dips/sprays; VAC = vaccine; COM = combination of multiple types.

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