During the transition period (the last weeks of gestation and first weeks of lactation), dairy cows face important physiological, metabolic and immunological challenges, which, if not successfully overcome, will impact their productive and reproductive performance. To face these challenges (nutritional and energy requirements imposed by colostrum and lactogenesis, inflammation, infection), cows launch homeorhetic and homeostatic mechanisms. However, these adaptation mechanisms do not guarantee that the cow will have a successful transition period. So it is not surprising that the highest incidence of diseases in dairy cattle is observed in the first 10 days postpartum (Ingvartsen et al, 2003; LeBlanc et al, 2006).
Almost a century ago, it was discovered that episodes of peripartum ataxia, initially known as milk fever, were explained by a drop in blood calcium concentrations (clinical hypocalcaemia). Subsequently, classic epidemiological studies, such as that of Curtis et al (1985), associated clinical hypocalcaemia with the incidence of other typical peripartum diseases (dystocia, retained placenta, metritis, ketosis, displaced abomasum and mastitis). This led to hypocalcaemia being considered a health disorder, which opened a ‘gateway’ to other diseases, and its establishment as a key condition that can determine the failure of the transition period and, consequently, the productive life of the cow (Goff, 2014). For decades, hypocalcaemia has attracted the attention of not only veterinarians, producers and nutritionists, but also researchers and companies (pharmaceutical, nutrition or health support).
The detrimental effects of clinical hypocalcaemia, the incidence of which has declined significantly in confined production systems through prepartum nutritional management (<3% in American herds; USDA-NAHMS, 2014), are currently beyond discussion. However, the definition of subclinical hypocalcaemia (blood calcium concentration threshold and timing after calving) and its implications on production, reproduction and health remain a controversial topic. Compared with clinical hypocalcaemia, the incidence of subclinical hypocalcaemia is relatively high. Reinhardt et al (2011) reported a 40% prevalence of subclinical hypocalcaemia (serum calcium <2.00 mmol/l) in the first 48 hours postpartum in 480 US herds (1462 cows sampled); while Rodríguez et al (2017) reported a prevalence of 78% (serum calcium <2.14 mmol/l) between the first 24–48 hours postpartum in six Spanish herds (764 cows sampled). Unfortunately, there is no published definitive data on the prevalence of clinical and subclinical hypocalcaemia in UK or Irish dairy herds. Currently ongoing research in Teagasc will provide figures on spring-calving pasture-based dairy herds.
Subclinical hypocalcaemia has traditionally been defined as blood calcium concentrations <2.00 mmol/l (<8.0 mg/dl). This definition was proposed by Dr Oetzel (University of Wisconsin, USA; personal communication) three decades ago, based on his knowledge and field experience, and although it lacked experimental validation, it was widely adopted by the sector. In the last decade, several epidemiological studies have evaluated the associations between blood calcium concentrations after parturition and production, reproduction or health parameters. In some studies, researchers have identified which cut-off points best predicted the parameters studied and in others they have used predetermined cut-off points (based on previous studies or definitions accepted by the sector). This has resulted in a wide range of cut-off points suggested to define subclinical hypocalcaemia. More recent research suggests that subclinical hypocalcaemia should be defined based on blood calcium concentration at 4 days postpartum, and introduces the term dyscalcemia, referring to cows that do not recover from reduced blood calcium concentration by this day post-partum, likely because of a limited capacity adapting to lactation (Hernandez and McArt, 2023).
Subclinical hypocalcaemia and production
The studies summarised here reported variable and even contradictory associations between postpartum blood calcium concentrations and milk production. These associations, as well as some of the factors that may explain the variation between studies (cut-off point and time relative to calving at subclinical hypocalcaemia definition), are described in Table 1. In general, the studies that measure blood calcium concentrations on day 1 or 2 after calving found that low calcium levels are associated with greater milk production. However, when blood calcium concentrations are determined in subsequent days, no associations were found or the observed associations had a negative connotation (low calcium levels are associated with lower milk production).
Table 1. Summary of the associations between subclinical hypocalcaemia and milk production reported in studies published in recent years.
| Study | Milk production compared to cows above cut-point1 | Total calcium cut-point (mmol/l) | Day postpartum |
|---|---|---|---|
| Chapinal et al, 2012 | -2.6 kg/d | ≤2.10* | <7 |
| McArt and Neves, 2020 | -3.2 kg/d2 | >1.77 and ≤2.20* | ≤1 and 4 |
| Seely et al, 2021 | -6.0 kg/d2 | >1.95 and ≤2.20 | 1 and 4 |
| Neves et al, 2018a | -1.8 kg/d2 | ≤2.20* | 4 |
| Menta et al, 2021 | –3 | ND4 | 3 |
| Neves et al, 2018a | –3 | ND4 | 2 to 3 |
| Martinez et al, 2012 | –3 | ≤2.14 | ≤3 |
| Rodríguez et al, 2017 | –3 | ≤2.14 | 1 to 2 |
| Chamberlin et al, 2013 | –3 | <2.00 | ≤1 |
| Menta et al, 2021 | +1.5 kg/d | ≤2.04* | 2 |
| Venjakob et al, 2018 | +0.8 kg/d2 | <2.10* | <2 |
| Jawor et al, 2012 | +5.7 kg/d | ≤1.80 | ≤1 |
| McArt and Neves, 2020 | +4.5 kg/d2 | ≤1.77 and >2.20* | ≤1 and 4 |
| Neves et al, 2018a | +2.6 kg/d2 | ≤1.77* | ≤1 |
| Valldecabres and Silva-del-Río, 2021 | +1.4 kg/d2 | ≤2.18* | ≤1 |
| Neves et al, 2018b | +1.1 kg/d2 | ≤1.77* | <0.5 |
The evaluation time for milk yield varied by study.
2Effect on multiparous.
3No association was detected.
4Cut-point not determined because of no statistical evidence of association.
*Cut-point determined within the study for its association with milk yield. Lack of asterisk indicates cut-point determined within the study for its association with parameters other than milk yield or from other sources.
The association between milk production and blood calcium concentration during peripartum was described by Goff et al (2002) in a study that included cows with intact udders and mastectomised cows. This association has also been demonstrated in studies in which milk production was reduced either by modifying the postpartum milking strategy or by inhibiting the lactogenesis signal (Vanacker et al, 2017; Valldecabres et al, 2022). Furthermore, some studies have found that high milk production in the previous lactation is a risk factor for subclinical hypocalcaemia (Neves et al, 2017; Valldecabres and Silva-del-Río, 2021). Therefore, it is possible that the drop in blood calcium concentration around parturition simply reflects the abrupt increase in calcium requirements associated with the synthesis of colostrum and milk. Low blood calcium concentration later may reflect the inability of homeorhetic and homeostatic mechanisms to cope with those calcium requirements. However, it must be taken into account that low concentrations of calcium in the blood can also be the result of low intake, inflammation or disease processes (Horst et al, 2021). The variability and contradiction in the reported associations suggest that postpartum blood calcium concentrations are unlikely to be directly responsible for milk production.
Subclinical hypocalcaemia and reproduction
In the literature, associations between postpartum blood calcium concentration and reproductive parameters suggest either no association or an association with a negative connotation (low calcium is associated with worse reproductive performance). The associations between postpartum blood calcium concentrations and pregnancy after first service, as well as the cut-off point and time relative to calving used to define subclinical hypocalcaemia are presented in Table 2. Low calcium concentrations in postpartum blood have also been associated with a delay in the return of ovarian cyclicity, a greater number of open days and a decreased risk of pregnancy in general (Martinez et al, 2012; Caixeta et al, 2017; Rodríguez et al, 2017; Umaña Sedó et al, 2018; Venjakob et al, 2018; Valldecabres and Silva-del-Río, 2021). However, other studies have evaluated these same associations without finding statistically significant results (Chamberlin et al, 2013; Wilhelm et al, 2017; Neves et al, 2018b).
Table 2. Summary of the associations between subclinical hypocalcaemia and pregnancy to first service reported in studies published in recent years.
| Study | Odds/risk of pregnancy to first service | Total calcium cut-point (mmol/l) | Day postpartum |
|---|---|---|---|
| Chapinal et al, 2012 | -30% | ≤2.20* | <7 |
| Seely and McArt, 2022 | -25%1 | ≤2.20 | 4 |
| Caixeta et al, 2017 | -63% | <2.15 | 1, 2 and 3 |
| Venjakob et al, 2018 | -44% | ≤1.90 | <2 |
| Umaña Sedó et al, 2018 | -64% | <2.00 | ≤1 |
| Valldecabres and Silva-del-Río, 2021 | -36%1 | <1.94* | ≤1 |
| Umaña Sedó et al, 2018 | –2 | ≤2.14 | 7 |
| Martinez et al, 2012 | –2 | ≤2.14 | ≤3 |
| Neves et al, 2018b | –2 | ND2 | <0.5 |
| Wilhelm et al, 2017 | –2 | ≤2.00 | <2 hours |
Effect on multiparous.
2No association was detected.
3Cut-point not determined because of no statistical evidence of association.
*Cut-point determined within the study for its association with milk yield. Lack of asterisk indicates cut-point determined within the study for its association with parameters other than milk yield or from other sources.
Although it is not clear how postpartum blood calcium can interfere with reproductive performance, it is worth highlighting the role of calcium in the maturation and activation processes of oocytes during fertilisation (Homa, 1995; He et al, 1997; Swann and Parrington, 1999). Furthermore, as will be discussed in the next section, hypocalcaemia has been associated with a higher incidence of diseases that affect the reproductive tract, which in turn are associated with alterations in reproductive performance (van Werven et al, 1992; Giuliodori et al, 2013a; 2013b). Therefore, it is possible that the association between blood calcium concentration and reproductive performance is the combination of the direct and indirect effects of calcium on different aspects related to reproduction.
Subclinical hypocalcaemia, health and culling
Studies that evaluated associations between subclinical hypocalcaemia and health found no association or that this association had a negative connotation (low calcium levels are associated with a higher incidence of disease). It is important to note that comparison between studies is difficult, as data analysis methods and definitions of subclinical hypocalcaemia and diseases varied between them. In studies in which associations have been detected in terms of probability, subclinical hypocalcaemia during the first week postpartum has been associated with up to 8.4 times greater probability of developing a displaced abomasum, 5.5 times greater probability of developing ketosis, 3.4 times more likely to have a retained placenta, and 4.3 times more likely to develop metritis (Melendez et al, 2004; Chapinal et al, 2011; Seifi et al, 2011; Martinez et al, 2012; Rodríguez et al, 2017; Wilhelm et al, 2017; Neves et al, 2018a; Venjakob et al, 2019). However, no study has been found that reports a statistically significant association between clinical mastitis and subclinical hypocalcaemia (Chamberlin et al, 2013; Rodríguez et al, 2017; Wilhelm et al, 2017; Neves et al, 2018b; Menta et al, 2021). The studies evaluated have suggested that the associations between serum calcium concentration and the diseases described may be as a result of the role of calcium in muscle contraction and the function of the immune system (Ebashi and Endo, 1968; Ducusin et al, 2003; Kimura et al, 2006).
The association between subclinical hypocalcaemia and the risk of culling has been evaluated in seven of the studies already presented in this article. It is worth noting that six of these studies have reported a higher risk of culling for cows with subclinical hypocalcaemia (Seifi et al, 2011; Martinez et al, 2012; Roberts et al, 2012; Wilhelm et al, 2017; Neves et al, 2018b; Venjakob et al, 2018; Menta et al, 2021). This result is not surprising considering the associations reported for health and reproductive performance. However, although the majority of studies agree in their observations, it would be incorrect to conclude that low calcium levels after calving are the cause of herd elimination, since the studies were not designed to establish causality.
Discussion
As this article shows, the definition of subclinical hypocalcaemia is not a topic beyond discussion and today we do not have a definition whose applicability in the field is guaranteed. The incorporation into the definition of subclinical hypocalcaemia of terms referring to the time after calving and the persistence of low calcium levels, as recently suggested (transient, persistent, chronic or delayed subclinical hypocalcaemia), seems to be the path to the identification of the pathological form of subclinical hypocalcaemia. Nevertheless, further research must follow to describe the biological relationship between the evaluated variables (eg milk yield, reproduction) and blood calcium concentration.
Descriptive epidemiological studies such as those presented here are useful to provide indications about associations between different parameters of interest. However, it must be taken into account that they do not establish cause–effect relationships since they are not controlled clinical trials and their results can only be discussed as presumably causal associations. Thus from the work presented here, one cannot discern whether hypocalcaemia is the cause, a contributing factor or a consequence for impaired performance. To strongly support causal relationships from observational studies, homogeneity in the results of the studies is needed. Reasons that may explain the lack of homogeneity in the results of the studies described here include differences in experimental design, such as the definition of subclinical hypocalcaemia (cut-off point and time after calving) and analytical methods (statistical and laboratory), as well as study sample size which must provide the required statistical power in order to allow for drawing conclusions in relation to the presence or absence of associations.
Conclusions
To this day there continues to be no definition of subclinical hypocalcaemia which can clearly be described as pathological or causative of undesired outcomes. Subclinical hypocalcaemia was traditionally defined as blood calcium concentrations <2.00 mmol/l; however, epidemiological studies carried out in the last decade suggest other cut-off points and highlight the complexity of the associations between blood calcium concentrations, production, reproduction and health. Based on current evidence, it seems that postpartum calcium concentration and subclinical hypocalcaemia should be considered as a sign (a reflection of high calcium demand [physiological or pathological] or low calcium intake or absorption) within a set of factors that determine the success of the transition from pregnant to lactating dairy cow.
KEY POINTS
- There is not a definition of subclinical hypocalcaecmia whose applicability in the field is guaranteed.
- Subclinical hypocalcaemia early after calving cannot be described as pathological or causative of undesired outcomes.
- Epidemiological studies do not establish cause–effect relationships.