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Uterine Inertia due to Severe Selenium Deficiency in a Parturient Mare
Journal Pre-proof Uterine inertia due to severe selenium deficiency in a parturient mare Nicolás Busse, DVM, Benjamín Uberti, DVM, MS PII:
S0737-0806(19)30594-5
DOI:
https://doi.org/10.1016/j.jevs.2019.102845
Reference:
YJEVS 102845
To appear in:
Journal of Equine Veterinary Science
Received Date: 8 August 2019 Revised Date:
9 October 2019
Accepted Date: 8 November 2019
Please cite this article as: Busse N, Uberti B, Uterine inertia due to severe selenium deficiency in a parturient mare, Journal of Equine Veterinary Science (2019), doi: https://doi.org/10.1016/ j.jevs.2019.102845. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
1
Nicolás Busse, DVM
2
Benjamín Uberti, DVM, MS
3
From the Institute of Veterinary Clinical Sciences, Universidad Austral de Chile, Valdivia,
4
Chile, 5090000.
5
Address: Universidad Austral de Chile, Independencia 641, Valdivia, Chile, 5090000.
6
Corresponding author: Dr. Benjamin Uberti ([email protected]).
7 8
Uterine inertia due to severe selenium deficiency in a parturient mare
9 10
Keywords: uterine inertia, dystocia, selenium deficiency, glutathione peroxidase.
11
Summary/Abstract:
12
A 12-year-old, multiparous parturient show jumper embryo-recipient mare presented at a
13
veterinary hospital for evaluation of mild colic, seven days past her due date and with a
14
dilated cervix. Gastrointestinal or metabolic abnormalities and fetal maldisposition were
15
excluded as causes of dystocia, and a diagnosis of uterine inertia was made. There was no
16
uterine response to oxytocin treatment. A live filly was obtained via caesection, and severe
17
selenium deficiency was eventually confirmed in the mare, her offspring, and in the herd of
18
origin. The filly was born with severe white muscle disease and required intensive
19
treatment. This report suggests that selenium deficiency is an underlying cause of equine
20
uterine inertia in the absence of other causes of dystocia.
21 22 23 24
25
1. Introduction
26
Causes of dystocia in mares are multiple; some of the most commonly reported are head or
27
limb malposture, posterior presentation, other miscellaneous fetal maldispositions,
28
contracted forelimb tendons, inadequate foal-to-birth canal size ratio, foal malformations,
29
insufficient cervical dilation, birth canal or cervical stricture, pelvic fracture, and primary
30
uterine inertia [1]. In a study, primary inertia corresponded to a mere 2.4% (n=2/166) of
31
dystocia cases over a period of 13 years. Causes of inertia were not reported, but all cases
32
underwent caesarean section [1]. Similarly, an older retrospective study mentions uterine
33
inertia as the cause of 2% (n=2/150) of all referred dystocias between 1977 and 1994 in two
34
North American veterinary teaching hospitals [2].
35
Uterine inertia can be both the cause or the result of dystocia [3,4]. Primary uterine inertia
36
is the inability of the uterus to execute coordinated myometrial contractions and
37
successfully eject content. Main causes described across numerous species are
38
hypocalcemia, hormonal imbalances at parturition, overstretching of uterine tissues (as seen
39
in hydrops allantois, twinning and oversized fetuses), myometrial degeneration resulting
40
from bacterial infection, or failure to respond to contraction signals [5–7]. Inertia can be a
41
consequence of premature deliveries in which adequate hormonal interactions fail to occur
42
properly [8,9]. Secondary uterine inertia is a failure to contract the myometrium due to
43
fatigue after prolonged labor [3,10]. Treatments for this disorder depend on the underlying
44
cause, and these include calcium supplementation, oxytocin administration, fetal mutation,
45
and/or cesarean section to resolve the dystocia [8].
46
So far, no categorical association between myometrial dysfunction in horses and other
47
known systemic muscular diseases (e.g. vitamin E deficiency, selenium deficiency, white
48
muscle disease) has been established in peer-reviewed literature. Some authors have peered
49
into the molecular mechanisms of selenoproteins in humans and mice [11–14], but solid
50
research on an equine model is still required. This report describes a case of uterine inertia
51
and selenium deficiency in a parturient mare.
52 53
54
2. Materials and methods
55
2.1. Case description
56
A 12-year-old, 550 kg, multiparous embryo-transfer recipient show-jumping mare with a
57
body condition score (BCS) of 5/9 in the Henneke BCS scale was referred to a teaching
58
hospital due to mild colic signs with a duration of three hours [15]. The mare originated
59
from a herd in Chilean Patagonia, was kept on pasture, and was seven days past her due
60
date. The owners reported no consumption of Festuca spp. nor presence of said species on
61
the farm of origin. Clinical examination was within normal limits, barring a mildly elevated
62
heart rate. Gastrointestinal causes of colic were ruled out (through physical examination,
63
nasogastric intubation, rectal palpation and abdominal ultrasound), and obstetrical
64
examination was commenced. The mare was examined rectally, and the foal was confirmed
65
to be alive and in anterior presentation, dorsosacral position with normal posture. Vaginal
66
examination revealed a dilated cervix, confirming stage I of parturition, although uterine
67
contractions where not detected neither during rectal nor vaginal examination. There were
68
no signs of prepubic tendon rupture or laxity, or compromise of the abdominal press. A
69
clinical diagnosis of primary uterine inertia was reached, warranting clinico-pathological
70
exploration of metabolic disturbances through blood gasometry, complete blood count
71
(CBC), and intraerythrocytic glutathione peroxidase (GPX) activity, respectively. Venous
72
blood gasometry showed no noteworthy alterations. Ionic calcium concentration was 1.62
73
mmol/L (reference values [RV]: 1.40-1.74 mmol/L). Extracellular sodium (138 mM; RV:
74
136-142) and potassium (4.2 mM; RV: 2.2-4.6) were within normal limits. CBC revealed
75
mild hemoconcentration (packed cell volume 43%, RV: 27-42), normal fibrinogen (20 g/L,
76
RV: <50), and mild mature neutrophilia (14,900 leucocytes/µL, RV: 7,200-14,400; 11,622
77
neutrophils/µL, RV: 2,200-6,100). Intraerythrocytic GPX was markedly decreased (22 U/g
78
Hb; RV: 130-270).
79
2.2. Treatment and outcome
80
After excluding metabolic abnormalities, the mare received empiric treatment with
81
oxytocin (3 injections of 0.05 IU/kg, intravenously, once every 10 minutes) without any
82
noticeable therapeutic response. Due to the foal’s high genetic value and absence of
83
progression of labor, surgical intervention was decided, and a live filly was delivered
84
through ventral midline laparotomy caesection. The mare recovered from general
85
anesthesia appropriately, but showed severe muscular weakness and prolonged decubitus.
86
Follow-up bloodwork revealed hyperfibrinogenemia (60 g/L; RV: <50), along with
87
moderate leukocytopenia (3,400 leucocytes/µL, RV: 7,200-14,400), mild left shift and
88
marked lymphocytopenia (374 lymphocytes/µL, RV: 1,500-6,500). Serum biochemistry
89
revealed hepatopathy, including an increase in gamma-glutamyltransferase (GGT) (121
90
U/L; RV: 12-62), glutathion dehydrogenase (GD) (16; RV: 1-7), and total bilirubin (89
91
µmol/L; RV: 7-47). Creatinine kinase was mildly increased (1,360 U/L; RV: 40-140), and
92
creatinine was minimally decreased (83 µmol/L; RV: 85-115). The placenta passed hours
93
after delivery, and showed no macroscopic abnormalities. The mare’s clinical progression
94
was unsatisfactory, and the owner declined further therapeutics due to her limited value as
95
an embryo recipient, preferring to concentrate investment in the filly. Thus, the mare was
96
euthanized 48 hours after surgery, and necropsy was declined.
97
Subsequentially, the filly was successfully treated for severe white muscle disease, with an
98
intraerythrocytic GPX value of 68 U/g Hb (RV: 130-270) at birth; she was discharged with
99
a favorable prognosis 60 days after birth and was reported to be healthy on follow-up two
100
years later.
101
Further exploration of the selenium nutritional status in the herd of origin confirmed
102
selenium deficiency in two of four other broodmares, through sampling of intraerythrocytic
103
glutathione peroxidase, and a history of clinical and subclinical nutritional mineral
104
deficiencies over the past few years.
105 106
3. Discussion
107
This report describes a previously unreported clinical manifestation of uterine inertia
108
associated with severe selenium deficiency in a mare. In organic systems, selenium is
109
considered a trace element and is mainly found in the amino acids selenocysteine and
110
selenomethionine. These are integral to the function of the antioxidant enzyme glutathione
111
peroxidase family, as well as other selenoproteins like deiodinases, involved in the
112
activation and inactivation of thyroid hormones [16]. Glutathione peroxidases guarantee
113
the metabolization of hydroperoxides that are produced as a byproduct of respiratory
114
oxidative reactions, which if left unprocessed lead to cellular damage [17]. Thus, clinical
115
manifestations of selenium deficiency are understood to be the consequence of chronic
116
oxidative damage, and among others, include myodegeneration (white muscle disease),
117
steatitis, hepatopathy, and impairment of immune function [18–20]. Selenium deficiency
118
has also been associated to increased incidence of retention of placenta and metritis in large
119
animal species, which may well be due to myometrial dysfunction and impaired uterine
120
contraction [18]. Interestingly, laboratory results by Chen et al (2019) show that decreasing
121
amounts of selenium in uterine smooth muscle tissue lead to a dephosphorylation of
122
phosphorylated myosin light chains (critical process in smooth muscle contraction due to
123
its inherent lack of troponin [21,22]), ultimately negatively affecting muscle contraction
124
[12,14]. Guo et al (2013) measured blood and tissue selenium concentrations in mice
125
populations after supplementation with diets containing different amounts of selenium
126
(lower than normal, normal and higher than normal), and found that values in blood and
127
uterine tissue were significantly higher in the reinforced diet group than the control group,
128
and significantly lower in the selenium deficient diet. The increase was proportional to the
129
amount of time over which these diets were administered (medium term: 20 days, and long
130
term: 40 and 60 days), but blood selenium levels stabilized after 40 days of
131
supplementation [12]. This proves that uterine selenium varies depending on dietary
132
provision, and provides an interesting starting point for research on this topic, and a
133
foothold for considering selenium deficiency as an etiology for uterine inertia across
134
species, and eventually its involvement in other related smooth muscle disorders [11].
135
Diagnosis of selenium deficiency in equid species can be challenging; whole selenium
136
blood levels can change significantly over short period of time depending on dietary intake,
137
and as such may not reflect true nutritional status. Intraerythrocytic glutathione peroxidase
138
concentration reflects historic selenium nutrition more accurately, and correlates well with
139
whole blood selenium [23,24]. Historical data of herd selenium supplementation, or
140
evidence of low selenium concentration in the forage used on the premises may also be of
141
use. Some regions will be more prone to these nutritional deficiencies depending on forage
142
availability, season and geographical location. Selenium in acidic soils of volcanic origin
143
adopts forms of poor bioavailability to plants, thereby compromising availability to animals
144
[27,28]. Moreover, sulfur in volcanic soil competitively hinders selenium uptake by plants
145
[29]. In southern Chile, a region with intense volcanic activity, horses and cattle regularly
146
experience selenium deficiency [30,31]. In this case, the farm of origin was located in the
147
vicinity of Osorno volcano, and selenium deficiency was confirmed and therapeutically
148
addressed in other animals of the herd. The nutritional status of vitamin E, another
149
important antioxidant, is also influenced by its provenance, since it is higher on fresh
150
pastures than in preserved roughage [25,26]. In this case, the herd was kept on fresh pasture
151
the year round, which makes vitamin E deficiency unlikely.
152
Regarding the interaction between mares and their offspring, white muscle disease is well
153
described in equine neonates [27,32]. Karren et al (2010) have reported that selenium
154
deficiency in either the mother or the foal indicates that the other is also affected by this
155
nutritional deficiency [24]. This case report provides an excellent example of this
156
relationship, given that the filly was born with severe white muscle disease and required
157
intensive treatment during the neonatal period. This also stresses the importance of routine
158
monitoring of maternal selenium status in order to avoid periparturient problems.
159
Histopathologic examination of the mare’s myometrial tissue was not performed,
160
regrettably because the recipient mare had limited economical value and the owner declined
161
further diagnostics. We encourage fellow clinicians to do so, as well as to assess selenium
162
status when encountering unexplainable dystocias in parturient mares, either through
163
measurement of whole blood selenium or intraerythrocytic GPX. Exploration of selenium
164
nutritional status should also be extended to the herd of origin. In conclusion, this case
165
suggests that selenium deficiency may be an underlying cause of myometrial dysfunction
166
and uterine inertia in the equine species, in the absence of other causes of dystocia.
167 168
References:
169
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Guo M, Lv T, Liu F, Yan H, Wei T, Cai H, et al. Dietary selenium influences calcium release and activation of MLCK in uterine smooth muscle of rats. Biol Trace
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Zhou J, Li C, Gu G, Wang Q, Guo M. Selenoprotein N Was Required for the
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Chen CJ, Xiao P, Chen Y, Fang R. Selenium Deficiency Affects Uterine Smooth
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Mice. Biol Trace Elem Res 2019. doi:10.1007/s12011-019-01677-8.
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1983;15:371–2. doi:10.1111/j.2042-3306.1983.tb01826.x.
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Schweizer U, Schlicker C, Braun D, Kohrle J, Steegborn C. Crystal structure of
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mammalian selenocysteine-dependent iodothyronine deiodinase suggests a
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Malevu TD, et al. A Summary of New Findings on the Biological Effects of
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adult horses1. J Anim Sci 2013;91:3702–15. doi:10.2527/jas.2012-5819.
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Montgomery JB, Wichtel JJ, Wichtel MG, McNiven MA, McClure JT, Markham F,
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et al. Effects of selenium source on measures of selenium status and immune
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function in horses. Can J Vet Res 2012;76:281–91.
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[21]
Bremel R. Myosin linked calcium regulation in vertebrate smooth muscle. Nature 1974;252:405–7. doi:10.1038/252405a0.
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Grand RJ, Perry S V, Weeks RA. Troponin C-Like Proteins (Calmodulins) from
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Mammalian Smooth Muscle and Other Tissues. Biochem J 1979;177:521–9.
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Czech Republic. Acta Vet Brno 2005;74:369–75.
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Ludvíková E, Pavlata L, Vyskoâil M, Jahn P. Selenium Status of Horses in the
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Karren BJ, Thorson JF, Cavinder CA, Hammer CJ, Coverdale JA. Effect of selenium
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supplementation and plane of nutrition on mares and their foals: Selenium
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concentrations and glutathione peroxidase. J Anim Sci 2010;88:991–7.
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doi:10.2527/jas.2008-1743.
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[25]
Bruhn JC, Oliver JC. Effect of Storage on Tocopherol and Carotene Concentrations
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in Alfalfa Hay. J Dairy Sci 1978;61:980–2. doi:10.3168/JDS.S0022-0302(78)83677-
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mares and foals during different seasons. J Anim Sci 1988;66:1418–1423.
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Maenpaa PH, Koskinen T, Koskinen E. Serum profiles of vitamins A, E and D in
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al. White muscle disease in foals: focus on selenium soil content. A case series.
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BMC Vet Res 2017;13:121. doi:10.1186/s12917-017-1040-5.
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De Temmerman L, Waegeneers N, Thiry C, Du Laing G, Tack F, Ruttens A.
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Selenium content of Belgian cultivated soils and its uptake by field crops and
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vegetables. Sci Total Environ 2014;468–469:77–82.
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Boyazoglu PA, Jordan RM, Meade RJ. Sulfur-Selenium-Vitamin E Interrelations in
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Rioseco M, Noro M, Chihuailaf R, Wittwer F. Selenium metabolic status and
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response to supplementation in grazing Chilean-Criollo horses. Rev MVZ Cordoba
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2013;18:3822–8.
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[31]
Contreras P, Wittwer F, Matamoros R, Mayorga I, Schaik G. Effect of grazing pasture with a low selenium content on the concentrations of triiodothyronine and
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thyroxine in serum, and GSH-Px activity in erythrocytes in cows in Chile. N Z Vet J
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2005;53:77–80. doi:10.1080/00480169.2005.36472.
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[32]
Löfstedt J. White muscle disease of foals. Vet Clin North Am Equine Pract 1997;13:169–85.
Highlights: •
Uterine inertia was confirmed in an embryo-recipient mare seven days after her due date, after ruling out other causes of dystocia.
•
Severe selenium deficiency was confirmed in the mare, as well as in her offspring and other broodmares in the herd of origin.
•
Selenium deficiency has been implicated as a cause of abortion and metritis in large animals. This report suggests that it is also a cause of uterine inertia in the equine species.
•
This mineral deficiency should be considered in the preventive management of mares in high-risk areas, as well as in the diagnostic route of individuals with dystocia.
CRediT (Contributor Roles Taxonomy) author statement: The authors contributed equally during the process of elaboration of the manuscript, and here we break down the main roles fulfilled during it: Nicolas Busse: Investigation, Writing – Original draft preparation, Writing – Reviewing and edition Benjamin Uberti: Conceptualization, Writing – Reviewing and edition, Supervision
Animal welfare and ethical statement: The case described in this report received the best available quality of medical care according to Universidad Austral de Chile’s School of Veterinary Sciences. Publication was pursued with the owner’s consent.
Funding statement: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest statement: The authors declare no conflicts of interest.
S0737-0806(19)30594-5
DOI:
https://doi.org/10.1016/j.jevs.2019.102845
Reference:
YJEVS 102845
To appear in:
Journal of Equine Veterinary Science
Received Date: 8 August 2019 Revised Date:
9 October 2019
Accepted Date: 8 November 2019
Please cite this article as: Busse N, Uberti B, Uterine inertia due to severe selenium deficiency in a parturient mare, Journal of Equine Veterinary Science (2019), doi: https://doi.org/10.1016/ j.jevs.2019.102845. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
1
Nicolás Busse, DVM
2
Benjamín Uberti, DVM, MS
3
From the Institute of Veterinary Clinical Sciences, Universidad Austral de Chile, Valdivia,
4
Chile, 5090000.
5
Address: Universidad Austral de Chile, Independencia 641, Valdivia, Chile, 5090000.
6
Corresponding author: Dr. Benjamin Uberti ([email protected]).
7 8
Uterine inertia due to severe selenium deficiency in a parturient mare
9 10
Keywords: uterine inertia, dystocia, selenium deficiency, glutathione peroxidase.
11
Summary/Abstract:
12
A 12-year-old, multiparous parturient show jumper embryo-recipient mare presented at a
13
veterinary hospital for evaluation of mild colic, seven days past her due date and with a
14
dilated cervix. Gastrointestinal or metabolic abnormalities and fetal maldisposition were
15
excluded as causes of dystocia, and a diagnosis of uterine inertia was made. There was no
16
uterine response to oxytocin treatment. A live filly was obtained via caesection, and severe
17
selenium deficiency was eventually confirmed in the mare, her offspring, and in the herd of
18
origin. The filly was born with severe white muscle disease and required intensive
19
treatment. This report suggests that selenium deficiency is an underlying cause of equine
20
uterine inertia in the absence of other causes of dystocia.
21 22 23 24
25
1. Introduction
26
Causes of dystocia in mares are multiple; some of the most commonly reported are head or
27
limb malposture, posterior presentation, other miscellaneous fetal maldispositions,
28
contracted forelimb tendons, inadequate foal-to-birth canal size ratio, foal malformations,
29
insufficient cervical dilation, birth canal or cervical stricture, pelvic fracture, and primary
30
uterine inertia [1]. In a study, primary inertia corresponded to a mere 2.4% (n=2/166) of
31
dystocia cases over a period of 13 years. Causes of inertia were not reported, but all cases
32
underwent caesarean section [1]. Similarly, an older retrospective study mentions uterine
33
inertia as the cause of 2% (n=2/150) of all referred dystocias between 1977 and 1994 in two
34
North American veterinary teaching hospitals [2].
35
Uterine inertia can be both the cause or the result of dystocia [3,4]. Primary uterine inertia
36
is the inability of the uterus to execute coordinated myometrial contractions and
37
successfully eject content. Main causes described across numerous species are
38
hypocalcemia, hormonal imbalances at parturition, overstretching of uterine tissues (as seen
39
in hydrops allantois, twinning and oversized fetuses), myometrial degeneration resulting
40
from bacterial infection, or failure to respond to contraction signals [5–7]. Inertia can be a
41
consequence of premature deliveries in which adequate hormonal interactions fail to occur
42
properly [8,9]. Secondary uterine inertia is a failure to contract the myometrium due to
43
fatigue after prolonged labor [3,10]. Treatments for this disorder depend on the underlying
44
cause, and these include calcium supplementation, oxytocin administration, fetal mutation,
45
and/or cesarean section to resolve the dystocia [8].
46
So far, no categorical association between myometrial dysfunction in horses and other
47
known systemic muscular diseases (e.g. vitamin E deficiency, selenium deficiency, white
48
muscle disease) has been established in peer-reviewed literature. Some authors have peered
49
into the molecular mechanisms of selenoproteins in humans and mice [11–14], but solid
50
research on an equine model is still required. This report describes a case of uterine inertia
51
and selenium deficiency in a parturient mare.
52 53
54
2. Materials and methods
55
2.1. Case description
56
A 12-year-old, 550 kg, multiparous embryo-transfer recipient show-jumping mare with a
57
body condition score (BCS) of 5/9 in the Henneke BCS scale was referred to a teaching
58
hospital due to mild colic signs with a duration of three hours [15]. The mare originated
59
from a herd in Chilean Patagonia, was kept on pasture, and was seven days past her due
60
date. The owners reported no consumption of Festuca spp. nor presence of said species on
61
the farm of origin. Clinical examination was within normal limits, barring a mildly elevated
62
heart rate. Gastrointestinal causes of colic were ruled out (through physical examination,
63
nasogastric intubation, rectal palpation and abdominal ultrasound), and obstetrical
64
examination was commenced. The mare was examined rectally, and the foal was confirmed
65
to be alive and in anterior presentation, dorsosacral position with normal posture. Vaginal
66
examination revealed a dilated cervix, confirming stage I of parturition, although uterine
67
contractions where not detected neither during rectal nor vaginal examination. There were
68
no signs of prepubic tendon rupture or laxity, or compromise of the abdominal press. A
69
clinical diagnosis of primary uterine inertia was reached, warranting clinico-pathological
70
exploration of metabolic disturbances through blood gasometry, complete blood count
71
(CBC), and intraerythrocytic glutathione peroxidase (GPX) activity, respectively. Venous
72
blood gasometry showed no noteworthy alterations. Ionic calcium concentration was 1.62
73
mmol/L (reference values [RV]: 1.40-1.74 mmol/L). Extracellular sodium (138 mM; RV:
74
136-142) and potassium (4.2 mM; RV: 2.2-4.6) were within normal limits. CBC revealed
75
mild hemoconcentration (packed cell volume 43%, RV: 27-42), normal fibrinogen (20 g/L,
76
RV: <50), and mild mature neutrophilia (14,900 leucocytes/µL, RV: 7,200-14,400; 11,622
77
neutrophils/µL, RV: 2,200-6,100). Intraerythrocytic GPX was markedly decreased (22 U/g
78
Hb; RV: 130-270).
79
2.2. Treatment and outcome
80
After excluding metabolic abnormalities, the mare received empiric treatment with
81
oxytocin (3 injections of 0.05 IU/kg, intravenously, once every 10 minutes) without any
82
noticeable therapeutic response. Due to the foal’s high genetic value and absence of
83
progression of labor, surgical intervention was decided, and a live filly was delivered
84
through ventral midline laparotomy caesection. The mare recovered from general
85
anesthesia appropriately, but showed severe muscular weakness and prolonged decubitus.
86
Follow-up bloodwork revealed hyperfibrinogenemia (60 g/L; RV: <50), along with
87
moderate leukocytopenia (3,400 leucocytes/µL, RV: 7,200-14,400), mild left shift and
88
marked lymphocytopenia (374 lymphocytes/µL, RV: 1,500-6,500). Serum biochemistry
89
revealed hepatopathy, including an increase in gamma-glutamyltransferase (GGT) (121
90
U/L; RV: 12-62), glutathion dehydrogenase (GD) (16; RV: 1-7), and total bilirubin (89
91
µmol/L; RV: 7-47). Creatinine kinase was mildly increased (1,360 U/L; RV: 40-140), and
92
creatinine was minimally decreased (83 µmol/L; RV: 85-115). The placenta passed hours
93
after delivery, and showed no macroscopic abnormalities. The mare’s clinical progression
94
was unsatisfactory, and the owner declined further therapeutics due to her limited value as
95
an embryo recipient, preferring to concentrate investment in the filly. Thus, the mare was
96
euthanized 48 hours after surgery, and necropsy was declined.
97
Subsequentially, the filly was successfully treated for severe white muscle disease, with an
98
intraerythrocytic GPX value of 68 U/g Hb (RV: 130-270) at birth; she was discharged with
99
a favorable prognosis 60 days after birth and was reported to be healthy on follow-up two
100
years later.
101
Further exploration of the selenium nutritional status in the herd of origin confirmed
102
selenium deficiency in two of four other broodmares, through sampling of intraerythrocytic
103
glutathione peroxidase, and a history of clinical and subclinical nutritional mineral
104
deficiencies over the past few years.
105 106
3. Discussion
107
This report describes a previously unreported clinical manifestation of uterine inertia
108
associated with severe selenium deficiency in a mare. In organic systems, selenium is
109
considered a trace element and is mainly found in the amino acids selenocysteine and
110
selenomethionine. These are integral to the function of the antioxidant enzyme glutathione
111
peroxidase family, as well as other selenoproteins like deiodinases, involved in the
112
activation and inactivation of thyroid hormones [16]. Glutathione peroxidases guarantee
113
the metabolization of hydroperoxides that are produced as a byproduct of respiratory
114
oxidative reactions, which if left unprocessed lead to cellular damage [17]. Thus, clinical
115
manifestations of selenium deficiency are understood to be the consequence of chronic
116
oxidative damage, and among others, include myodegeneration (white muscle disease),
117
steatitis, hepatopathy, and impairment of immune function [18–20]. Selenium deficiency
118
has also been associated to increased incidence of retention of placenta and metritis in large
119
animal species, which may well be due to myometrial dysfunction and impaired uterine
120
contraction [18]. Interestingly, laboratory results by Chen et al (2019) show that decreasing
121
amounts of selenium in uterine smooth muscle tissue lead to a dephosphorylation of
122
phosphorylated myosin light chains (critical process in smooth muscle contraction due to
123
its inherent lack of troponin [21,22]), ultimately negatively affecting muscle contraction
124
[12,14]. Guo et al (2013) measured blood and tissue selenium concentrations in mice
125
populations after supplementation with diets containing different amounts of selenium
126
(lower than normal, normal and higher than normal), and found that values in blood and
127
uterine tissue were significantly higher in the reinforced diet group than the control group,
128
and significantly lower in the selenium deficient diet. The increase was proportional to the
129
amount of time over which these diets were administered (medium term: 20 days, and long
130
term: 40 and 60 days), but blood selenium levels stabilized after 40 days of
131
supplementation [12]. This proves that uterine selenium varies depending on dietary
132
provision, and provides an interesting starting point for research on this topic, and a
133
foothold for considering selenium deficiency as an etiology for uterine inertia across
134
species, and eventually its involvement in other related smooth muscle disorders [11].
135
Diagnosis of selenium deficiency in equid species can be challenging; whole selenium
136
blood levels can change significantly over short period of time depending on dietary intake,
137
and as such may not reflect true nutritional status. Intraerythrocytic glutathione peroxidase
138
concentration reflects historic selenium nutrition more accurately, and correlates well with
139
whole blood selenium [23,24]. Historical data of herd selenium supplementation, or
140
evidence of low selenium concentration in the forage used on the premises may also be of
141
use. Some regions will be more prone to these nutritional deficiencies depending on forage
142
availability, season and geographical location. Selenium in acidic soils of volcanic origin
143
adopts forms of poor bioavailability to plants, thereby compromising availability to animals
144
[27,28]. Moreover, sulfur in volcanic soil competitively hinders selenium uptake by plants
145
[29]. In southern Chile, a region with intense volcanic activity, horses and cattle regularly
146
experience selenium deficiency [30,31]. In this case, the farm of origin was located in the
147
vicinity of Osorno volcano, and selenium deficiency was confirmed and therapeutically
148
addressed in other animals of the herd. The nutritional status of vitamin E, another
149
important antioxidant, is also influenced by its provenance, since it is higher on fresh
150
pastures than in preserved roughage [25,26]. In this case, the herd was kept on fresh pasture
151
the year round, which makes vitamin E deficiency unlikely.
152
Regarding the interaction between mares and their offspring, white muscle disease is well
153
described in equine neonates [27,32]. Karren et al (2010) have reported that selenium
154
deficiency in either the mother or the foal indicates that the other is also affected by this
155
nutritional deficiency [24]. This case report provides an excellent example of this
156
relationship, given that the filly was born with severe white muscle disease and required
157
intensive treatment during the neonatal period. This also stresses the importance of routine
158
monitoring of maternal selenium status in order to avoid periparturient problems.
159
Histopathologic examination of the mare’s myometrial tissue was not performed,
160
regrettably because the recipient mare had limited economical value and the owner declined
161
further diagnostics. We encourage fellow clinicians to do so, as well as to assess selenium
162
status when encountering unexplainable dystocias in parturient mares, either through
163
measurement of whole blood selenium or intraerythrocytic GPX. Exploration of selenium
164
nutritional status should also be extended to the herd of origin. In conclusion, this case
165
suggests that selenium deficiency may be an underlying cause of myometrial dysfunction
166
and uterine inertia in the equine species, in the absence of other causes of dystocia.
167 168
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169
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Highlights: •
Uterine inertia was confirmed in an embryo-recipient mare seven days after her due date, after ruling out other causes of dystocia.
•
Severe selenium deficiency was confirmed in the mare, as well as in her offspring and other broodmares in the herd of origin.
•
Selenium deficiency has been implicated as a cause of abortion and metritis in large animals. This report suggests that it is also a cause of uterine inertia in the equine species.
•
This mineral deficiency should be considered in the preventive management of mares in high-risk areas, as well as in the diagnostic route of individuals with dystocia.
CRediT (Contributor Roles Taxonomy) author statement: The authors contributed equally during the process of elaboration of the manuscript, and here we break down the main roles fulfilled during it: Nicolas Busse: Investigation, Writing – Original draft preparation, Writing – Reviewing and edition Benjamin Uberti: Conceptualization, Writing – Reviewing and edition, Supervision
Animal welfare and ethical statement: The case described in this report received the best available quality of medical care according to Universidad Austral de Chile’s School of Veterinary Sciences. Publication was pursued with the owner’s consent.
Funding statement: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest statement: The authors declare no conflicts of interest.