The purpose of this study was to describe the epidemiology of subclinical ketosis (SCK) in dairy cows in early lactation and determine the association of (1) days in milk (DIM) at onset of SCK, and (2) blood β-hydroxybutyrate (BHBA) concentration at onset of SCK with development of displaced abomasum (DA) and removal from herd in the first 30 DIM, conception to first service, days to conception within 150 DIM, and early lactation milk yield. Cows from 4 freestall dairy herds (2 in New York and 2 in Wisconsin) were each tested 6 times for SCK from 3 to 16 DIM using the Precision Xtra meter (Abbott Laboratories, Abbott Park, IL). Subclinical ketosis was defined as a BHBA concentration of 1.2 to 2.9 mmol/L. Mixed-effects multivariable Poisson regression was used to assess DA, removal from herd, and conception to first service. Semiparametric proportional hazards models were used to evaluate days to conception, and repeated-measures ANOVA was used to evaluate milk yield in the first 30 DIM. A total of 741 of 1,717 (43.2%) eligible cows had a least one BHBA test of 1.2 to 2.9 mmol/L. Peak incidence of SCK occurred at 5 DIM, when 22.3% of cows had their first SCK-positive test. Peak prevalence of SCK occurred at 5 DIM, when 28.9% of cows had a SCK-positive test. Median time from first positive SCK test until BHBA test <1.2 mmol/L was 5d. Cows first testing SCK positive from 3 to 5 DIM were 6.1 times more likely [95% confidence interval (CI) = 2.3 to 16.0] to develop a DA than cows first testing SCK positive at 6 DIM or later. Cows first testing SCK positive from 3 to 7 DIM were 4.5 times more likely (95% CI = 1.7 to 11.7) to be removed from the herd, were 0.7 times as likely (95% CI = 0.6 to 0.8) to conceive to first service, and produced 2.2 kg less milk per day for the first 30 DIM than cows first testing positive at 8 DIM or later. Each 0.1 mmol/L increase in BHBA at first SCK-positive test increased the risk of developing a DA by a factor of 1.1 (95% CI = 1.0 to 1.2), increased the risk of removal from herd by a factor of 1.4 (95% CI = 1.1 to 1.8), and was associated with a decrease in milk production by 0.5 kg/d for the first 30 DIM. These results show that time of onset and BHBA concentration of first SCK-positive test are important indicators of individual cow performance.

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The purpose of this study was to determine the effect of oral propylene glycol (PG) administration on ketosis resolution and milk yield in cows diagnosed with subclinical ketosis (SCK). Cows from 4 freestall dairy herds (2 in New York and 2 in Wisconsin) were each tested 6 times for SCK from 3 to 16 d in milk on Mondays, Wednesdays, and Fridays. Subclinical ketosis was defined as a β-hydroxybutyrate (BHBA) concentration of 1.2 to 2.9 mmol/L, [corrected] and clinical ketosis was defined as ≥ 3.0 mmol/L. [corrected]. Cows with SCK were randomized to the treatment group (oral PG) or control group (no PG); treatment cows were drenched with 300 mL of PG once daily from the day they tested 1.2 to 2.9 mmol/L [corrected] until the day they tested <1.2 mmol/L. [corrected]. Outcomes evaluated for all farms included time from SCK until BHBA test <1.2 mmol/L [corrected] or until BHBA test ≥ 3.0 mmol/L. [corrected]. Individual milk weights for the first 30 d of lactation were evaluated for the 3 farms monitoring daily milk. Semiparametric proportional hazards models were used to evaluate time to event outcomes; repeated-measures ANOVA was used to assess milk weights. A total of 741 of 1,717 (43.2%) eligible enrolled cows had at least one BHBA test of 1.2 to 2.9 mmol/L. [corrected]. Of these, 372 were assigned to the treatment group and 369 to the control group. Based on hazard ratios, PG-treated cows were 1.50 times more likely (95% confidence interval=1.26 to 1.79) to resolve their SCK and 0.54 times less likely (95% confidence interval=0.34 to 0.86) to develop clinical ketosis than control cows. Across the 3 herds measuring individual milk weights, treated cows produced 0.23 kg more milk per milking in the first 30 d of lactation than control cows, for a total difference of 0.69 kg/cow per day. After identification of a treatment by herd interaction, stratification by herd showed that treated cows produced more milk per milking on farm A (0.44 kg) and farm B (0.53 kg) in the first 30 d of lactation than control cows, for a total difference of 1.34 and 1.59 kg/d, respectively; milk production did not differ (0.02 kg per milking) between the 2 groups on farm D. These results show the positive effects of oral PG administration in fresh cows with SCK by helping to resolve SCK and preventing clinical ketosis. In addition, oral PG improves milk yield during early lactation in cows diagnosed with SCK.

The purpose of this study was to develop a deterministic economic model to estimate the costs associated with (1) the component cost per case of hyperketonemia (HYK) and (2) the total cost per case of HYK when accounting for costs related to HYK-attributed diseases. Data from current literature was used to model the incidence and risks of HYK (defined as a blood β-hydroxybutyrate concentration≥1.2 mmol/L), displaced abomasa (DA), metritis, disease associations, milk production, culling, and reproductive outcomes. The component cost of HYK was estimated based on 1,000 calvings per year; the incidence of HYK in primiparous and multiparous animals; the percent of animals receiving clinical treatment; the direct costs of diagnostics, therapeutics, labor, and death loss; and the indirect costs of future milk production losses, future culling losses, and reproduction losses. Costs attributable to DA and metritis were estimated based on the incidence of each disease in the first 30 DIM; the number of cases of each disease attributable to HYK; the direct costs of diagnostics, therapeutics, discarded milk during treatment and the withdrawal period, veterinary service (DA only), and death loss; and the indirect costs of future milk production losses, future culling losses, and reproduction losses. The component cost per case of HYK was estimated at $134 and $111 for primiparous and multiparous animals, respectively; the average component cost per case of HYK was estimated to be $117. Thirty-four percent of the component cost of HYK was due to future reproductive losses, 26% to death loss, 26% to future milk production losses, 8% to future culling losses, 3% to therapeutics, 2% to labor, and 1% to diagnostics. The total cost per case of HYK was estimated at $375 and $256 for primiparous and multiparous animals, respectively; the average total cost per case of HYK was $289. Forty-one percent of the total cost of HYK was due to the component cost of HYK, 33% to costs attributable to metritis, and 26% to costs attributable to DA. The high total cost of HYK at reported incidences of 40 to 60% highlights the importance of appropriate transition cow nutrition and management to decrease the effect of HYK.

Our aim in this Journal of Dairy Science centennial review is to describe the evolution of focus on metabolic indicators, from discovery and description to evaluation at the individual cow and subsequently herd levels, over the past 100 yr. Furthermore, we discuss current and future technologies that will be used in the dairy industry to utilize these indicators widely going forward. Knowledge of chemical changes in various fluids (e.g., blood, urine, and milk) accompanying numerous metabolic disease states in the dairy cow has existed since almost the beginning of the Journal of Dairy Science 100 yr ago. However, only during the last 25 yr have these metabolic indicators been developed into useful tools for cow- and herd-level monitoring for disease and management. From the 1920s through the 1940s, our understanding of the changes in blood chemistry accompanying milk fever and ketosis increased, as did our understanding of the underlying biology. In the 1950s and 1960s, workers studying ketosis and energy metabolism began to evaluate changes in lipid metabolism reflected by concentrations of circulating nonesterified fatty acids; furthermore, initial development occurred for on-farm tests of milk ketones. During the 1970s, blood metabolic profiling was applied to dairy farms but found to be of varied and limited usefulness. The turning point occurred when large epidemiologic studies of periparturient cow disease were pioneered in the United States, Canada, and Europe in the 1980s; these studies further solidified our understanding of risk factors and epidemiological interrelationships among disease, production, and reproduction. In the early 1990s, scientists first incorporated indicators of metabolic health into large observational studies and determined important epidemiological relationships between these indicators and outcomes of interest. This field of study blossomed during the 2000s as several research groups conducted multiple investigations into metabolic indicators related to energy metabolism and began to develop cow-level thresholds and herd-level alarms for use in monitoring and management. This work was accompanied by additional studies to validate point-of-care instruments that could be used to implement these strategies at the cow and herd levels. Work in the 2000s continued to identify and evaluate other physiological indicators of inflammation and oxidative stress; however, these have yet to be incorporated into large-scale cohort studies. Finally, use of technology (e.g., activity monitoring, cow-monitoring collars and tags, milk-based analysis using Fourier transform infrared spectroscopy) continues to receive significant attention going forward to eventually allow for real-time and automatic monitoring of metabolic indicators and improved health and herd management on dairy farms.

The purpose was to determine important dry and calving period predictors of (1) a cow developing hyperketonemia at any time between 3 and 16 d in milk (DIM) and (2) a cow having hyperketonemia at her first β-hydroxybutyrate (BHBA) test after calving (between 3 and 5 DIM). Cows from 4 freestall dairy herds [2 in New York (NY) and 2 in Wisconsin] were enrolled at 266 d carried calf. Precalving data included body condition score, locomotion score, and blood nonesterified fatty acids (NEFA) concentration; calving-associated data included previous days carried calf, calving ease, calf sex, twins, stillbirth, and parity. Cows were each tested 6 times for hyperketonemia from 3 to 16 DIM on Mondays, Wednesdays, and Fridays using the Precision Xtra meter (Abbott Laboratories, Abbott Park, IL). Hyperketonemia was defined as a blood BHBA concentration of ≥1.2 mmol/L. Multivariable fixed-effects Poisson regression models were developed to predict the probability of a cow developing hyperketonemia between either 3 and 16 DIM or at her first BHBA test. As only the NY herds had precalving NEFA data, each prediction model was developed twice: once with data from all 4 herds (n=1,672) and once with data from only the NY herds (n=544). For the models with data from all 4 herds, increased body condition score group and an interaction between advanced parity and herd were important predictors of hyperketonemia development at any time from 3 to 16 DIM; calf sex (male), herd, and an advanced parity by increased body condition score group interaction were important predictors of hyperketonemia development between 3 and 5 DIM. The 4-herd models had a 64 and 78% predictive concordance for hyperketonemia between 3 and 16 DIM and at first BHBA test, respectively. For the models with data from the NY herds only, increased NEFA, calf sex (male), advanced parity, and herd were found to be important predictors of hyperketonemia development at any time from 3 to 16 DIM; increased NEFA, calf sex (male), decreased calving ease, stillbirth, and advanced parity were important predictors of having hyperketonemia at first BHBA test. The NY models had a 69 and 87% predictive concordance, respectively. These results may help identify at-risk animals and improve dry-cow management strategies before hyperketonemia develops.

The objectives of this study were to characterize the epidemiology of subclinical hypocalcemia (SCH) in Holstein dairy cows by assessing the temporal associations of plasma Ca concentrations in the first 4 d in milk (DIM) with the risk of cows being diagnosed with metritis or displaced abomasum (or both), and milk production across the first 15 wk of lactation. A prospective cohort study was conducted in 2 dairy herds in New York State, in which cows had a blood sample collected daily for the first 4 DIM. A total of 396 Holstein cows (137 primiparous and 259 multiparous) were enrolled. Multivariable Poisson regression models were built to evaluate the associations of plasma Ca concentration at each of the 4 d following parturition with the risk of primiparous cows being diagnosed with metritis and multiparous cows being diagnosed with metritis, displaced abomasum, or both. Similarly, generalized linear mixed models were built to evaluate the associations of plasma Ca concentration with milk production across the first 15 wk of lactation. Plasma Ca concentration was assessed on a continuous scale in all models; dichotomization and SCH classification only occurred in the final models if the Ca concentration variable was meaningful by creating an optimized threshold based on receiver operating characteristic curve analysis. Plasma Ca concentration assessed at 1 DIM was not associated with the risk of metritis in primiparous cows, but an association was observed at 2, 3, and 4 DIM (critical thresholds were plasma Ca concentration ≤2.15, 2.10, and 2.15 mmol/L, respectively). Plasma Ca concentration was associated with the risk of metritis or displaced abomasum diagnosis (or both) for 2nd parity animals at 2 DIM (threshold ≤1.97 mmol/L), and at 4 DIM for 3rd and greater lactations (threshold ≤2.20 mmol/L). Reduced plasma Ca concentration was associated with higher milk production when assessed at 1 DIM in primiparous and multiparous cows, and lower milk production when assessed at 4 DIM in multiparous cows only. For primiparous cows, plasma Ca concentration was not associated with lower milk production at any of the DIM assessed. In conclusion, assessments of SCH at the individual cow level must take into account the DIM of Ca concentration measurement and parity of the cow, as the epidemiology of the disorder was demonstrated to be highly dependent on these variables. This study advances the knowledge of the epidemiology of SCH and better establishes thresholds for optimizing SCH diagnosis.