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Chronic postpartum uterine infection detrimentally affects subsequent fertility. Nonsteroidal anti-inflammatory drugs (NSAID) are used to alleviate pain and treat inflammatory conditions in transition dairy cows with varying success. To screen the efficacy of NSAID in the absence of animal experiments, we have established an in vitro model to study uterine inflammation. Inflammation was induced in cultured bovine endometrial epithelial cells by challenging cells with an inflammation cocktail: lipopolysaccharide and proinflammatory cytokines, interleukin-1β (IL1β) and tumor necrosis factor α (TNFα). Release of the inflammation markers, serum amyloid A (SAA) and α-1-acid glycoprotein (αAGP), was measured by ELISA. Concentration of these markers was used to indicate the effectiveness in dampening inflammation of 5 NSAID: meloxicam, flunixin meglumine, aspirin, ketoprofen, and tolfenamic acid. Three NSAID, meloxicam, flunixin meglumine, and tolfenamic acid, were successful at dampening the release of SAA and αAGP into cell-culture supernatant, and the corresponding treated cells were selected for down-stream mRNA expression analysis. Expression of 192 genes involved in regulation of inflammatory pathways were investigated using Nanostring. Of the genes investigated, 81 were above the mRNA expression-analysis threshold criteria and were included in expression analysis. All SAA genes investigated (SAA2, SAA3, M-SAA3.2) were upregulated in response to the inflammation cocktail, relative to mRNA expression in control cells; however, AGP mRNA expression was below the expression analysis threshold and was, therefore, excluded from analysis. Treatment with NSAID downregulated genes involved in regulating chemokine signaling (e.g., CXCL2, CXCR4, CXCL5, and CXCL16) and genes that regulate the eicosanoid pathway (e.g., LTA4H, PTGS2, PLA2G4A, and PTGDS). Of the 5 NSAID investigated, meloxicam, flunixin meglumine, and tolfenamic acid are recommended for further investigation into treatment of postpartum uterine inflammation. The results from this study confirm the immunomodulatory properties of the endometrial epithelium in response to inflammatory stimuli and suggest that NSAID may be beneficial in alleviating uterine inflammation., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

The physiology of the dairy cow while transitioning from pregnancy to lactation is complex, with multifactorial processes studied extensively for the role they play in manifestation of disease along with associated economic losses and compromised animal welfare. Manuscripts outlining associations among nutrition, production, physiology, and genetics variables and transition cow disorders are common in literature, with blood analytes that are central to energy metabolism (e.g., nonesterified fatty acids; NEFA, β-hydroxybutyrate; BHB) often reported. Immunity and inflammation have increasingly been explored in the pathogenesis and persistence of disorders, with cytokines and acute phase proteins well documented. However, most of these studies have involved cows fed total mixed rations, which may not always reflect profiles of blood analytes and other physiological indicators of transition cow health in grazing cows consuming fresh pasture. Considering the comparatively lesser characterization of these analytes and markers in pasture-based, seasonal-calving dairy cows, we compiled a database consisting of 2,610 cow lactations that span 20 yr of transition cow research in New Zealand. Using this database, analyte profiles from approximately 28 d precalving to 35 d postcalving were identified in dairy cows with a range of genetics, milk production potentials, and pasture-based farm management systems. These profiles characterize changes in energy reserves and metabolism (NEFA, BHB, glucose, insulin, growth hormone, insulin-like growth factor-1, leptin, body condition score, body weight), liver function (globulin, aspartate aminotransferase, glutamate dehydrogenase, gamma-glutamyl transpeptidase, bilirubin, cholesterol, liver triacylglycerides), protein metabolism (albumin, total protein, albumin:globulin ratio, creatinine, urea, creatine kinase), mineral balance (calcium, magnesium, phosphate, potassium, sodium, chloride, bicarbonate), inflammation (IL-1β, IL-6, haptoglobin, reactive oxygen species, total antioxidant capacity), and uterine health (polymorphonuclear cells, macrophage cells, vaginal discharge score). Temporal changes are generally consistent with previously characterized homeorhetic changes experienced by the dairy cow during the transition from pregnancy to lactation in both pastoral and housed systems. Some of the profiles had not previously been presented for pastoral systems, or in some cases, presented for either system. Our results indicate that moderate-yielding dairy cows undergo similar homeorhetic changes to high-yielding housed cows; however, differences in diet composition result in greater BHB concentrations than expected, based on their milk production and NEFA concentrations. In addition, most cows were able to transition to a state of higher energy requirement following calving, albeit with an increased metabolic challenge in the liver, and only a small percentage of cows were classified with severe hepatic lipidosis or severe hyperketonemia. Increases in metabolic function of the liver were accompanied by changes in indicators of the immune system and changes in mineral balance that, combined, probably reflect the innate response to the transition from gestation to lactation., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Hypocalcemia is a common metabolic disorder of transition dairy cows that is considered a gateway disease, increasing the risk of other health disorders and reducing cow performance. Clinical milk fever is associated with long periods of recumbency, and it is plausible that cows experiencing non-paretic hypocalcemia may spend more time lying; hence, lying behavior and activity measures may be useful in identifying at-risk cows. The objective of this study was to describe associations among blood calcium (Ca) status at calving and lying behavior and activity measures during the transition period in grazing dairy cows. Blood was sampled on the day of calving (d 0), and d 1, 2, 3, and 4 postcalving, and analyzed for total plasma Ca concentration. Twenty-four multiparous Holstein-Friesian and Holstein-Friesian × Jersey grazing dairy cows were classified, retrospectively, as clinically hypocalcemic (CLIN; blood Ca ≤ 1.4 mmol/L at 1 or more consecutive samplings within 48 h postcalving, but without parturient paresis). These cows were pair-matched (using milk production potential from their estimated breeding value for milk protein, mean body weight at wk -5 and -6 precalving, and, where possible, parity) with 24 cows classified as subclinically hypocalcemic (SUB; blood Ca > 1.4 and < 2.0 mmol/L at 2 consecutive samplings within 48 h postcalving), and 24 cows classified as normocalcemic (NORM; blood Ca ≥ 2.0 mmol/L at 3 consecutive samplings within 72 h postcalving). Lying behavior and activity were monitored using triaxial accelerometers from -21 to +35 d relative to calving. Data were summarized to calculate daily lying time (h/d), daily number of lying bouts (LB; no./d), mean LB duration (min/bout), and the number of steps taken (steps/d). On d 0, the CLIN group were less active and spent approximately 2.6 h longer lying than the SUB and NORM groups, particularly between 0200 and 1400 h. On d 0, the NORM group had fewer LB (16.3/d) than the SUB and CLIN groups (18.2 and 19.2/d, respectively). These differences in behavior were no longer detected 2 d postcalving, and no further differences were observed. The day before calving, the CLIN group spent 1.4 h longer lying down than did the SUB and NORM groups. Further, the relative change in steps from a precalving baseline period (d -14 to -7) until d 0 was positively, linearly associated with blood Ca concentration within 24 h postcalving. Future work should consider daily and temporal changes in behavior in individual cows to determine the potential for these measures to allow early detection of hypocalcemia., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

The objective of this study was to determine the economic costs associated with different reasons for cow culling or on-farm mortality in a pasture-based seasonal system. A bioeconomic model was developed to quantify costs associated with the different farmer-recorded reasons and timing of cow wastage. The model accounted for the parity and stage of lactation at which the cows were removed as well as the consequent effect on the replacement rate and average age structure of the herd. The costs and benefits associated with the change were quantified, including animal replacement cost, cull salvage value, milk production loss, and the profitability of altered genetic merit based on industry genetic trends for each parity. The total cost of cow wastage was estimated to be NZ$23,628/100 cows per year (NZ$1 = US$0.69) in a pasture-based system. Of this total cost, NZ$14,300/100 cows worth of removals were for nonpregnancy and unknown reasons, and another NZ$3,631/100 cows was attributed to low milk production, mastitis, and udder problems. The total cost for cow removals due to farmer-recorded biological reasons (excluding unknown, production, and management-related causes) was estimated to be NZ$13,632/100 cows per year. Of this cost, an estimated NZ$10,286/100 cows was attributed to nonpregnancy, mastitis, udder problems, calving trouble, and injury or accident. There is a strong economic case for the pasture-based dairy industries to invest in genetic, herd health, and production management research focused on reducing animal wastage due to reproductive failure, mastitis, udder problems, injuries or accidents, and calving difficulties., (Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Postpartum uterine inflammation (endometritis) in the dairy cow is associated with lower fertility at both the time of infection and after the inflammation has resolved. We hypothesized that aberrant DNA methylation may be involved in the subfertility associated with uterine inflammation. The objective of this study was to characterize genome-wide DNA methylation and gene expression in the endometrium of dairy cows with subclinical endometritis (SCE). Endometrial tissues were obtained at 29 days postpartum (n = 12), and microarrays were used to characterize transcription and DNA methylation. Analyses revealed 1,856 probes differentially expressed in animals with SCE (n = 6) compared with controls (CON, n = 6, P < 0.05, Storey Multiple testing correction) and 2,976 probes with significant correlation between gene expression and bacteriology score. No significant associations among DNA methylation and gene expression were detected. Analysis of transcription data using the Database for Annotation, Visualization, and Integrated Discovery and Gene Set Enrichment Analysis identified several pathways and processes enriched in SCE cows, with the majority related to the immune response. Furthermore, the top ontology terms enriched in genes that had expression data correlated to bacteriology score were: Defense response, inflammatory response, and innate immune response. Gene expression profiles in cows with subclinical endometritis in this study indicate that the immune response is activated, potentially resulting in a local proinflammatory environment in the uterus. If this period of inflammation is prolonged it could result in tissue damage or failure to complete involution of the uterus, which may create a suboptimal environment for future pregnancy., (Copyright © 2015 the American Physiological Society.)

Body condition score (BCS) is an assessment of a cow's body fat (and muscle) reserves, with low values reflecting emaciation and high values equating to obesity. The intercalving profile of BCS is a mirror image of the milk lactation profile. The BCS at which a cow calves, her nadir BCS, and the amount of BCS lost after calving are associated with milk production, reproduction, and health. Genetics, peripartum nutrition, and management are factors that likely interact with BCS to determine the risk of health disorders., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The objective of this study was to determine if the inflammation associated with subclinical endometritis (SCE) is a part of the mechanism by which reproductive performance is reduced in cows with this disease. If it is, reducing inflammation associated with SCE with a nonsteroidal antiinflammatory drug (NSAID) should reduce the severity [as measured by average polymorphonuclear cell (PMN) percentage] of uterine pathology and improve reproductive performance. It was also investigated whether the NSAID treatment reduced metabolic indicators of systemic inflammation previously reported to be altered in cows with SCE. Holstein-Friesian and Friesian-Jersey cross dairy cows (n=213) were paired by calving date and d-14 uterine PMN percentage and randomly assigned to 3 injections at intervals of 3 d of an NSAID (1.4 mg of carprofen/kg; n=104) between 21 and 31 d postpartum or left as untreated controls (n=109). Cows with ≥14% PMN (upper quartile of PMN percentage) in the cytological sample collected at d 14 postpartum were defined as having SCE. The average d-14 PMN percentage was low (9.9%) and a high self-cure rate of SCE (>90%) at d 42 was observed. Treatment with an NSAID reduced plasma concentrations of aspartate aminotransferase and increased pregnancy rate in SCE cows. However, no effect of the NSAID treatment was observed on PMN percentage at d 42, postpartum anovulatory interval, or milk production. Compared with cows without SCE, cows with SCE had lower plasma albumin concentration, albumin:globulin ratio, and body condition score, but higher nonesterified fatty acids on the day of calving. These results indicate that cows with SCE are experiencing a physiological dysfunction, including lower body condition, liver dysfunction, and greater metabolic challenge during the periparturient period. Further research is required to determine the effect of NSAID on SCE and to evaluate the influence of timing of drug application on treatment effectiveness., (Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

The primary objective of this study was to identify relationships between endometritis and metabolic state during the calving transition and early lactation periods. A subset of mixed age and breed dairy cows (n=78) from a seasonal, pasture-grazed herd of 389 cows was examined. The selected cows were grouped as having endometritis at d 42 postpartum or being unaffected by endometritis. Endometritis was defined as >6% (upper quartile) of uterine nucleated cells being polymorphonuclear cells (H-PMN; n=38); unaffected by endometritis was defined as ≤1% of nucleated cells being polymorphonuclear (L-PMN; n=40). Milk yield was determined at each milking, and milk composition (fat and protein) was determined at 2-wk intervals. Blood samples collected on d -14, 0 (d of calving), 4, 7, 14, 28, and 42 were analyzed for indicators of energy status (nonesterified fatty acids, glucose, and urea), liver function (albumin, globulin, glutamate dehydrogenase, and aspartate aminotransferase), inflammation (haptoglobin), and mineral status (Ca and Mg). Samples collected weekly from d 21 to 63 or 70 were analyzed for progesterone content. The postpartum anovulatory interval was defined to end on the first day postpartum that plasma progesterone concentration was ≥1 ng/mL. A greater percentage of H-PMN cows failed to ovulate before d 63 or 70 (34%) compared with L-PMN cows (10%), although the proportions of cows ovulating within either polymorphonuclear group was similar through d 56 postpartum. Plasma concentrations of albumin and the albumin:globulin ratio were consistently lower in H-PMN cows. Plasma Mg was lower, whereas glutamate dehydrogenase and aspartate aminotransferase were higher, in H-PMN cows during early lactation compared with L-PMN cows. Circulating metabolites indicative of energy status (nonesterified fatty acids, glucose, and urea) were not different between polymorphonuclear groups. Among 3- to 5-yr-old cows, daily milk yield for the first 42 d after calving was lower for H-PMN cows than for L-PMN cows. Among cows >5 yr old, protein percentage was lower in H-PMN cows compared with L-PMN cows. In summary, endometritis at 42 d postpartum in the herd studied was associated with an increased likelihood of remaining anovulatory. These cows had lower albumin concentrations throughout the calving transition period, perhaps indicating impaired liver function, with lower plasma Mg and evidence of hepatocellular damage in early lactation. Similar profiles of nonesterified fatty acids and glucose indicated that energy status was not a risk factor for endometritis., (Copyright © 2010 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to quantify the effect of periparturient body condition score (BCS) and body weight (BW) related traits on the incidence of calving dystocia and stillbirths, and to determine any consequent effect of dystocia and stillbirths on BCS, BW, milk production, udder health, and fertility in grazing Holstein-Friesian dairy cows. Up to 2,384 lactation records with data on calving dystocia or stillbirths were available from one research herd across 15 yr. Mixed models and generalized estimating equations were used to quantify all effects. Body condition score or BW 8 wk precalving or at calving, or change precalving did not significantly affect the odds of a difficult calving or stillbirth. Cows that experienced dystocia lost, on average, more BCS and BW between calving and nadir and had significantly reduced nadir BCS and BW. Incidence of stillbirths did not affect BCS in early lactation, although BW loss postpartum was greater following a stillbirth. A dystocia or stillbirth event was associated with reduced 60-d milk yield (42 and 52 kg less milk produced following a difficult calving or a stillbirth, respectively). The effect of stillbirth on milk yield was independent of dystocia. Cows that experienced dystocia had reduced milk concentration of fat, protein, and lactose, whereas average somatic cell score (natural logarithm of somatic cell count) in the first 60-d postpartum was elevated. There was no significant effect of dystocia or stillbirth on clinical mastitis, but pregnancy rates to first service and throughout the 12-wk breeding season were compromised in cows that had experienced difficulty at calving. The significance of the effects of stillbirth on somatic cell score and reduced fertility were mediated through its association with dystocia. In conclusion, periparturient BCS and BW within the range observed in the current study did not significantly affect incidence of dystocia and stillbirth, but these events negatively affected cow performance in early lactation.

Management, nutrition, production, and genetics are the main reasons for the decline in fertility in the modern dairy cow. Selection for the single trait of milk production with little consideration for traits associated with reproduction in the modern dairy cow has produced an antagonistic relationship between milk yield and reproductive performance. The outcome is a multi-factorial syndrome of subfertility during lactation; thus, to achieve a better understanding and derive a solution, it is necessary to integrate a range of disciplines, including genetics, nutrition, immunology, molecular biology, endocrinology, metabolic and reproductive physiology, and animal welfare. The common theme underlying the process is a link between nutritional and metabolic inputs that support complex interactions between the gonadotropic and somatotropic axes. Multiple hormonal and metabolic signals from the liver, pancreas, muscle, and adipose tissues act on brain centers regulating feed intake, energy balance, and metabolism. Among these signals, glucose, fatty acids, insulin-like growth factor-I, insulin, growth hormone, ghrelin, leptin, and perhaps myostatin appear to play key roles. Many of these factors are affected by changes in the somatotropic axis that are a consequence of, or are needed to support, high milk production. Ovarian tissues also respond directly to metabolic inputs, with consequences for folliculogenesis, steroidogenesis, and the development of the oocyte and embryo. Little doubt exists that appropriate nutritional management before and after calving is essential for successful reproduction. Changes in body composition are related to the processes that lead to ovulation, estrus, and conception. However, better indicators of body composition and measures of critical metabolites are required to form precise nutritional management guidelines to optimize reproductive outcomes. The eventual solution to the reduction in fertility will be a new strategic direction for genetic selection that includes fertility-related traits. However, this will take time to be effective, so, in the short term, we need to gain a greater understanding of the interactions between nutrition and fertility to better manage the issue. A greater understanding of the phenomenon will also provide markers for more targeted genetic selection. This review highlights many fruitful directions for research, aimed at the development of strategies for nutritional management of reproduction in the high-producing subfertile dairy cow.

The objective of the present study was to quantify the climatic, animal, and management factors influencing incidence of milk fever (MF) in cows exposed to grazing systems. Data were extracted on 4,469 calvings of multiparous cows in a seasonal calving research herd between 1970 and 2000. Climatic data during the calving period also were extracted for these years. Poisson regression was used to investigate the effect of climate on frequency of MF within year; the offset variable was the number of cows at risk for MF at that time. Generalized estimating equations, with cow included as a repeated effect, were used to quantify the effect of parturition-associated cow and management factors on the logit of the probability of MF. Both univariate and multivariate analyses were performed. Explanatory variables investigated included time of calving relative to the herd-year calving period, parity, body weight, breed of cow, body condition score at calving, weight and gender of the calf, incidence of twin calves, calving inductions, and calving assistance. Odds of recurring MF within cow, as well as the timing of MF relative to day of calving, was quantified using generalized estimating equations with cow included as a repeated effect. Results show significant effects of evaporation, minimum grass temperature, difference between ambient maximum and minimum temperature, and rainfall on the odds of MF occurring, with a greater incidence at greater evaporation, larger diurnal variation in air temperature, greater rainfall, and lesser grass minimum temperature. Cow factors, such as age, excessive or poor body condition score, and requirement for calving assistance increased the odds of MF; a lesser odds ratio was observed in cows hormonally induced to calve and those that had twin births. Results indicate that herd managers may identify the day of greatest risk for MF and cows that are at greatest risk of MF based on climatic, cow, and management factors.

It was hypothesized that a reduction in the dietary cation-anion difference (DCAD) before calving, combined with an increase in Ca intake after calving, would reduce the incidence of periparturient hypocalcaemia and increase milk production in pasture-based dairy cows. Cows (n = 40) were assigned to one of two DCAD levels before calving (i.e., +7 and +50 mEq/100 g). Each group was then assigned to one of two dietary Ca concentrations after calving (i.e., 1.0 and 0.7%) in a 2 x 2 factorial design. The lower DCAD resulted in a nonrespiratory reduction in systemic pH as indicated by a lower urine pH. This acidosis resulted in an increased concentration of Ca in urine before calving. The lower precalving DCAD helped prevent the decline in blood Ca caused by the onset of lactation, even though blood Ca concentration was lower before calving compared with cows receiving a high DCAD. Supplementation of cows with Ca after calving increased plasma Ca concentration on the day of calving and during the subsequent 14 d. Milk production was not affected by pre- or postcalving treatments.

A large emphasis on precalving magnesium supplementation has substantially reduced the incidence of clinical hypocalaemia in pasture-based systems. Survey data in the major pasture-based systems suggest a 2 to 4% incidence of parturient paresis, although this can vary considerably between farms. Detailed blood measurements under research conditions suggests that approximately 5% of cows are clinically hypocalcaemic (blood calcium < 1.4 mmol/l) and between 30 and 40% of cows are subclinically hypocalcaemic (plasma calcium < 2.0 mmol/l). Systems of control have traditionally been based on preventing the paretic cow, with more emphasis of late being placed on preventing hypocalcaemia. Preventative measures vary, but largely involve either supplementation with magnesium oxide pre-calving, supplementation with calcium carbonate during the colostrum period or a combination of magnesium supplementation precalving and calcium supplementation post-calving. In New Zealand, the use of commercial products that bind calcium is increasing precalving, but is still only practiced by a small percentage of farmers. The dietary cation-anion difference (DCAD) of pasture is so high and so variable that changes in DCAD sufficient to change blood pH are not practical and very difficult to achieve with consistency. The use of magnesium chloride and magnesium sulphate in preference to magnesium oxide, as precalving magnesium supplements, is increasing.

Hypocalcaemia or milk fever is a condition resulting from an insufficiency of plasma calcium to maintain proper body function and is probably the most prevalent mineral-related disorder faced by the transition cow. It is also referred to as parturient paresis or parturient paralysis due to the recumbency that accompanies the most common hypocalcaemia, that is hypocalcaemia that occurs at or around calving. Milk fever was first reported in Germany in 1793 and since then has been the study of many researchers because of its economic importance, reducing milk production by 7 to 14%, depending on the degree of severity. Its prevention has been addressed by different methods including deliberately changing the blood acid-base balance through supplementation of metabolically strong anions (chlorine and sulphur) in an attempt to improve calcium homeostasis in the periparturient cow. This adjustment to the systemic acid-base balance of the cow is difficult to achieve practically and consistently in pasture-based systems and recent research has questioned its efficacy in maintaining a periparturient eucalcaemia.