1 CONTACT Ky Pohler Ky.Pohler@ag.tamu.edu © 2025 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http:// creativecommons.org/licenses/by-nc/4.0/), permitting all noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Citation: Clinical Theriogenology 2025, 17, 11037, http://dx.doi.org/10.58292/CT.v17.11037 Review Report Highlighting factors contributing to pregnancy loss in beef cattle* Brette Poliakiwski, Damon Smith, Zachary Seekford, Ky Pohler Department of Animal Science, Texas A&M University, College Station, TX, USA Abstract Pregnancy loss in beef cattle remains a costly problem for producers, leading to diminished calf crop uniformity and reduced per- centages of cows with a calf at the end of calving season. Although several tools exist to ascertain pregnancy status, the first 30 days of pregnancy encompasses the period with the greatest proportion of pregnancy losses and these losses often occur before tradi- tional methods permit pregnancy determination. The ability to accurately predict pregnancy failure remains a major limitation. Blood-based assays detecting chemical changes in maternal circulation have provided insight into embryonic and fetal monitoring and are used to make predictions for pregnancy loss. Although there are certain unknown aspects to the etiology of pregnancy loss, there is growing body of work to identify physiological biomarkers within the maternal, paternal, and embryonic systems to clarify risk factors for pregnancy failure. This review highlights a few of the factors contributing to pregnancy loss and the rapidly evolving methods utilized to predict pregnancy failure. Further, this review highlights a few of the changes to parental physiology after expo- sure to various environmental factors, the consequences on the physiology of pregnancy and the likelihood of pregnancy success. Keywords: Cattle, pregnancy, placentation, maternal, sire, environmental Introduction1 Embryonic and fetal mortality remain as major issues in domestic livestock production. Although embryonic mortal- ity and pregnancy loss research have garnered industry-wide attention, a major limitation within is the inability to accu- rately predict pregnancy failure and determine early embry- onic and fetal viability. Additionally, predicting pregnancy loss in beef cattle is difficult in enterprises that are less intensely managed than dairy operations that collect data to compile reproductive outcomes. Early pregnancy contains several critical developmental milestones and pregnancy losses can occur throughout this period. There are continued discussions within reproductive physiology to determine the period of most substantial embryonic loss. Fertilization rates in beef cattle are estimated quite high (~ 90%) but attrition occurring throughout pregnancy indicated that the underly- ing issue of pregnancy loss extends beyond the period of suc- cessful conception.1 Indeed, embryonic mortality (0-45 days after insemination) is estimated to affect 54% of beef cattle after a single insemina- tion.1 Within this period, roughly 16% of this embryonic loss *Presented at the 2023 Society for Theriogenology conference, published after peer review. occurs between days 16-32 and ~ 6% of these losses occurs between days 29-45.1 Some suggest that embryonic mortality is most substantial between embryo hatching and elongation although others suggest that it is most substantial during and after maternal recognition of pregnancy and early placenta- tion.2,3 These periods of embryonic development encompass the processes of maternal recognition of pregnancy and early placentation, possibly indicating that pregnancy loss may be attributed to either failed embryonic signaling or improper placentation events. Therefore, the issue of pregnancy loss is likely multifactorial. Although the timing of embryonic mortality and pregnancy loss in cattle can vary substantially based on production sta- tus, parity, genetic composition, breeding method, and man- agement conditions there are apparent embryonic, maternal, paternal, and environmental factors known to contribute to pregnancy failure (Figure 1). Aim of this review is to highlight some of the current known and hypothesized contributions to pregnancy loss experienced in beef cattle and the evolving methods on how pregnancy loss is predicted. Measuring reproductive efficiency Before discussing various components of pregnancy loss, it is important to first understand how to measure and manage mailto:Ky.Pohler@ag.tamu.edu http://creativecommons.org/licenses/by-nc/4.0/ http://creativecommons.org/licenses/by-nc/4.0/ http://dx.doi.org/10.58292/CT.v17.11037 2 Citation: Clinical Theriogenology 2025, 17, 11037, http://dx.doi.org/10.58292/CT.v17.11037 these losses. Pregnancy determination is a vital tool to mea- sure reproductive efficiency; the generated data are used to directly monitor farm reproductive success or to indirectly study trends in national fertility. It has been estimated that pregnancy loss in beef cattle in the USA results in a gross loss of $3.7 billion in profit per year.4 Despite this, only 20% of USA beef operations utilize pregnancy diagnosis. Thus, there remains a clear disconnect between the financial benefits and the utilization of pregnancy data. The lack of adoption of pregnancy diagnosis likely stems from a lack of trained techni- cians, increased input costs associated with labor and service fees, the need for adequate handling facilities, and/or the effects of handling stress on cattle. Fortunately for producers, there are 3 primary methods to con- sider for pregnancy diagnosis; each method has advantages and disadvantages over the others. The most traditional method is transrectal palpation of uterine contents. Transrectal palpation is often completed by certified personnel at least 40 days after breeding and offers an affordable means to detect conceptus and associated membranes without the use of costly equip- ment. Despite the cost effectiveness of transrectal palpation, the accuracy of pregnancy determination remains dependent on the skill of the technician. The precise determination of aging via transrectal palpation before day 40 is dependent solely on the detection of the cardinal signs of pregnancy (displacement of the chorio-allantoic membrane, palpation of amniotic vesicle, palpation of fetus or palpation of placentomes).5 Although transrectal palpation of uterine contents are used to estimate age of pregnancy, this method is limited in its ability to accurately estimate embryonic viability as assessed by the heartbeat.6 Ultrasonography is becoming quickly adopted amongst beef producers. Unlike transrectal palpation of uterine contents, ultrasonography can determine pregnancy as early as 28 days after breeding and is a more accurate method to determine fetal age through the measurement of crown rump length.7,8 Ultrasonography also provides producers an earlier opportu- nity to make a management decision compared to transrectal palpation.6,7 Another benefit of ultrasonography is the ability to determine fetal sex from days 60-90 of pregnancy. Knowing fetal sex is an advantage for seedstock producers who can plan what sex of breeding animals they will market in upcoming sales. Although ultrasonography is becoming more economi- cal and more accurate as technology advances, it remains a costly tool for practitioners that imparts costs to producers. Likewise, although ultrasonography can detect pregnancy ear- lier than transrectal palpation of uterine contents, it does not prevent the possibility of loss after pregnancy diagnosis. Lastly, one of the newest technologies utilized for pregnancy determination are blood-based pregnancy tests. Similar to Figure 1. Proposed factors contributing to pregnancy loss in beef cattle; pregnancy loss is a multifactorial issue and is likely a reflection of inadequacy at the embryonic, maternal, paternal and environmental levels (EGA: Embryonic genome activation, MRP: maternal recognition of pregnancy, PAG: pregnancy associated glycoproteins, IFNT: interferon-tau, P4: progesterone PG: prostaglandins). http://dx.doi.org/10.58292/CT.v17.11037 Citation: Clinical Theriogenology 2025, 17, 11037, http://dx.doi.org/10.58292/CT.v17.11037 3 ultrasonography, blood or milk-based tests are performed as early as 28 days after breeding and rely on the detection of a family of proteins called pregnancy associated glycoprotein (PAG) in maternal circulation. Detectable concentrations of PAG are only present in maternal circulation when the animal is pregnant or just recently calved or aborted. One advantage of blood or milk tests is that producers do not require substantial training or, in the case of rapid tests, expensive equipment to perform. Additionally, blood or milk-based tests also offer preg- nancy status determination for operations that are located far away from a technician capable of performing transrectal palpa- tion or ultrasonography; furthermore, travel expenses for tech- nicians to get to an operation are eliminated. Blood or milk tests are performed either chute side or shipped to laboratories across the country for PAG quantification. Chute-side results are generated within 20 minutes, whereas blood shipped to the laboratory generally have results within a week. Therefore, the ability of producers to quickly make management decisions pertaining to pregnancy status relies on the type of test utilized. Commercially available blood-based pregnancy tests have true-positive rates of 93-98% and false-positive rates of 1-7%.9,10 Thus, one clear limitation of blood or milk-based pregnancy determination is the risk of false-positives for animals experi- encing embryonic mortality occurring after collection of blood or milk used for initial pregnancy status determination and the period of secondary confirmation via blood or milk test. Cows that recently experienced embryonic mortality or immediately after parturition maintained elevated concentrations of PAGs.11,12 Collectively, each of these methods of pregnancy determination are suited for various operations but each of them ultimately results in the same outcome, increased repro- ductive efficiency by determining nonpregnant status earlier. Ability to accurately determine pregnancy status allows produc- ers to make management decisions, ultimately improving farm profitability and sustainability of beef production. Embryonic contributions to pregnancy loss First week of pregnancy encompasses the greatest proportion of pregnancy loss in beef and dairy cattle.1,2 During this period there are major developmental milestones that are critical for pregnancy success such as fertilization, embryonic genome activation, blastocyst formation, and hatching from the zona pellucida. A meta-analysis compiling data from 12 studies investigating pregnancy loss in beef cattle through day 7 of pregnancy was 28.4% and within these studies, before day 4, pregnancy loss was 23%.1 In dairy cattle, it has been estimated that only ~ 50% of ovulated oocytes will generate viable embryos between days 6 and 8 after insemination.2 Given the large proportion of attrition occurring during the first week of pregnancy, discussing specific embryonic factors associated with pregnancy failure is warranted. Estimated rates of fertilization in beef and dairy cattle are pre- dicted to be ~ 90%, indicating that substantial losses occur after gametic syngamy.13-15 Although the consensus is that ovu- lated oocytes do not differ in the ability to undergo fertiliza- tion, given compliance with accurate artificial insemination (AI) techniques, there are factors prior to ovulation that can impact oocyte developmental competence. Indeed, manipu- lating the periovulatory hormonal environment can influence fertility outcomes. One such example is in cows that ovulated smaller follicles at estrus had fewer pregnancies per AI com- pared to cows that ovulated larger follicles.16 Evidence from dairy cattle indicated that follicular growth is altered when progesterone concentrations are lower, hindering oocyte mat- uration and ability to establish pregnancy.17 Although it should be acknowledged that many determinants of embry- onic competence are influenced by preovulatory factors, the activation of the embryonic genome also presents a critical period of embryonic mortality. Embryonic genome activation, also called the maternal-to-embryonic transition, is a transi- tory period occurring around the 8-16 cell stage of embryonic development whereby the early embryo degrades maternal RNAs and proteins and begins transcription and translation of the newly formed genomic products.18,19 The molecular mech- anisms regulating embryonic genome activation have yet to be fully elucidated; however, failure of the embryo to complete this transition results in the inability of the embryo to con- tinue. Collectively, identifying optimal periovulatory physiol- ogy and regulators of the maternal-embryonic transition present opportunities to improve embryonic survival and mit- igate pregnancy losses. The high incidence of pregnancy loss during the first weeks of pregnancy has driven concerted efforts to try and predict embry- onic competence to sustain pregnancy to term.20 These efforts have been focused on identifying biomarkers indicative of preg- nancy success during the preimplantation and postattachment periods of development. Early statistical models utilizing calv- ing data from more than 4,500 embryo transfers attempted to predict embryo survivability to term and revealed that only 50-70% of embryos and recipients are competent to result in a calf.21 These authors concluded that factors external to the embryo (e.g. recipient) are critical regulators to embryonic sur- vival or loss.21 As technology has advanced, the tools utilized to predict embryonic competence have also expanded. Indeed, the use of machine learning to incorporate highly detailed models with developmental outcomes has been explored to identify embryonic genes predictive of competence. One study that combined transcriptomic data from blastocysts of known developmental competence with transcriptomic data of long and short conceptuses identified differentially expressed genes amongst the populations and integrated these genes into path- ways predictive of embryonic competence and conceptus elon- gation.20 The 341 differentially expressed genes associated with embryonic competence were annotated to pathways relating to metabolic processes, glycolysis/gluconeogenesis, and glycero- lipid metabolism.20 Similarly, 669 genes associated with embry- onic incompetence were annotated to the spliceosome, RNA processing, and cell cycle regulation.20 Together, these authors suggest that specific transcriptional patterns within the first weeks of pregnancy are identified as predictors of embryonic success, but also, the pathways identified may reveal novel tar- gets for reducing pregnancy failure. The authors further utilized machine learning to discriminate differentially expressed genes into genes predictive of pregnancy success or failure and identi- fied 8 genes (CHSY1, GSTO1, TPI1, CCNA2, CDK7, EIF4A3, LSM4, and YWHAG); the first 3 are predicted to be expressed within competent blastocysts and last 5 expressed in incompe- tent blastocysts.20 Collectively, this work has provided insights into the molecular signature of embryos predicted to lead to pregnancy success. Further works remain to test the validity of these candidate biomarker genes and to interrogate the path- ways regulating embryonic competency; however, the increased utilization of next generation sequencing and machine learning will permit further understanding of the processes leading to pregnancy success. Failure to elicit maternal recognition of pregnancy Around day 16 of the normal estrous cycle, follicular estra- diol concentrations begin to increase that stimulate the actions of estrogen receptor alpha leading to increased http://dx.doi.org/10.58292/CT.v17.11037 4 Citation: Clinical Theriogenology 2025, 17, 11037, http://dx.doi.org/10.58292/CT.v17.11037 expression of oxytocin receptors in the endometrium, ulti- mately perpetuating pulsatile secretion of prostaglandin F2α (PGF2α).22 These PGF2α pulses act as the primary luteolytic signaling molecule causing regression of the corpus luteum, thus beginning a new estrous cycle. When a conceptus is present within the uterine lumen, however, interferon tau (IFNT) secreted by the trophoblast cells in the placenta work to block the luteolytic cascade and maintain the corpus luteum. This process, deemed maternal recognition of preg- nancy, is also heavily reliant on embryonic secreted factors. Although IFNT is primarily attributed to its role in cycle extension, IFNT also elicits robust changes in the local endo- metrial landscape and to peripheral physiology. For example, IFNT secreted by the conceptus will exit from the uterine vein and increase the expression of interferon stimulated genes (ISG) such as ISG15, MX1, MX2, and OAS1 in extrauterine tissues such as circulating blood cells and the corpus luteum compared to nonpregnant controls.23-25 The dynamic changes to extrauterine expression in ISGs have been utilized as a pre- dictor of pregnancy loss. Indeed, recent works have demon- strated an association between elevated concentrations of ISGs and pregnancy maintenance in dairy cattle.26 Currently, the physiological implication of IFNT-induced changes to maternal immune cells in the periphery are not clear. Transcriptomic analyses of peripheral leukocytes collected 21 days after embryo transfer have been conducted to compare between cows that maintained or lost pregnancy.27 Sequencing revealed that the top upregulated pathways were related to inflammatory chemokine activity and immune defense response, suggesting that IFNT has a role in modu- lating immune tolerance.27 The roles of conceptus-derived IFNT promoting immune tolerance and recognition of preg- nancy in extrauterine tissues require further study, and understanding the mechanisms of immune tolerance in cat- tle presents a unique opportunity to mitigate pregnancy fail- ure by identifying key regulatory pathways. Another consideration when discussing IFNT is the abun- dance or dose of IFNT secreted by the trophoblast cells. It is known that endometrium responds differently to shorter and longer conceptuses.28 This finding is interesting given recent in vitro data indicating that endometrial explants had dose- and period-dependent changes to gene expression in response to IFNT.29 Taken together, these data implied that inadequate or inappropriately timed secretion of IFNT by the conceptus can fail to elicit a response within the endometrium and ulti- mately fail to rescue corpus luteum. Thus, failure of the con- ceptus to secrete sufficient amounts of IFNT could contribute to pregnancy loss. Given that secretion of IFNT is dependent on the embryo, future studies should investigate whether the conceptus must secrete baseline concentrations of IFNT to elicit a maternal response. Lastly, although IFNT is known to induce changes to the endometrial transcriptome, endome- trium also responds to other secreted factors independent of IFNT.30 A novel experiment cultured endometrial explants with either a day 15 conceptus derived from in vitro fertiliza- tion, day 15 conceptus derived from AI, 100 ng/ml of recom- binant IFNT, or medium alone revealed 240 differentially expressed genes in endometrial explants cultured in the pres- ence of conceptus, regardless of origin.30 Indeed, infusion of conceptus-derived prostaglandins into the uterine lumen of cyclic ewes induced changes in the expression of classical Type I interferon-stimulated genes ISG15 and RSAD2.31 Collectively, roles of prostaglandins during the periattachment period war- rant further study. In particular, roles of prostaglandins secreted by the conceptus and the endometrium as they per- tain to attachment need further exploration. Attachment failure at the embryonic-maternal interface Although evidence strongly indicates that the proportion of pregnancy loss decreases as pregnancy progresses, the inci- dence of pregnancy loss during the late embryonic and early fetal period is limited in the characterization.1 This period of embryonic development occurs after maternal recognition of pregnancy ~ days 21-28 of pregnancy, encompassing the earli- est phases of placental apposition, adhesion, and attach- ment.32,33 During this period of pregnancy, the placental trophoblast cells begin to differentiate into 2 morphologically recognizable populations delineated by the number of nuclei (mononucleated or binucleated).32 Binucleated trophoblast cells comprise 15-20% of trophoblast cells and will migrate through microvillar junctions of the uterine luminal epithe- lium, ultimately forming a fetal-maternal syncytium.34 Trophoblast binucleate cells upon final maturation begin to rapidly express and secrete PAG.35 The PAG family of proteins represent a group of aspartic proteinases that are highly expressed products of the cetartiodactyla placenta.35 At the placental-epithelial interface, there is an abundance of PAG- positive cells beginning around day 21.33 Functional roles of PAG are still explored; a study treated endometrial explants isolated from pregnant and nonpregnant animals 18 days after estrus with an equal mixture of PAG 4, 6, and 9 resulted in transcriptional changes for proteins associated with matrix remodeling, chemokine production and prostaglandin release.36 Thus, changes elicited in response to PAG locally in the endometrium and peripherally need to be investigated. In particular, the immunomodulatory roles of PAG during the periattachment period warrant further study. As aforementioned, PAG concentrations within maternal cir- culation are an accurate marker to predict embryonic mortal- ity.37 Pregnant cows with higher peripheral concentrations of PAG experienced increased embryonic survival compared to those with lower circulating PAG concentrations (Figure 2).11,38 Additionally, it has been documented that cows undergoing late embryonic mortality had differing circulating PAG pat- terns compared to those that maintained pregnancy (Figure 2).11 Given that PAG concentrations in maternal circu- lation are associated with embryonic competence or mortal- ity, roles of PAG in the physiology of pregnancy competence are explored. Recent evidence has indicated that cows with higher placentome blood perfusion have elevated concentra- tions of circulating PAG compared to cows with lower placen- tome blood perfusion.39 In lactating dairy cattle, delayed increases in PAG was indicative of inappropriately timed or insufficient embryonic attachment.26 Collectively, the PAG- mediated physiological changes at the placental-maternal interface are still early in the characterization. The literature has established that PAGs, an embryonic product, are a strong measure of fetal monitoring and are incorporated in paramet- ric analyses to predict pregnancy failure. However, the specific molecular and cellular functions of PAG have not been com- pletely elucidated and therefore researchers are interested in understanding the roles of PAG in quintessential aspects of placentation, such as tissue remodeling. In summary, the embryo represents a major contributing fac- tor to the success or failure of pregnancy. Therefore, there are many pivotal risk periods for determining embryonic success for pregnancy. Current and future works should investigate and test more precise predictors of embryonic competence. Furthermore, understanding the molecular and cellular physi- ology regulating positive pregnancy outcomes could be used http://dx.doi.org/10.58292/CT.v17.11037 Citation: Clinical Theriogenology 2025, 17, 11037, http://dx.doi.org/10.58292/CT.v17.11037 5 to study the supplementation of factors that may be lacking in embryos progressing towards failure. Contributions of the maternal uterine environment to pregnancy loss Maternal-embryonic communication is critical in achieving reproductive success, and the uterus responds dynamically to the embryo throughout pregnancy. Secretion of specific pro- teins, hormones, and growth factors by the embryo and endo- metrium within the lumen are essential for the establishment and maintenance of pregnancy. Therefore, understanding this dialogue is necessary for elucidating the underlying reasons for pregnancy loss. The fundamental role of the endometrium prior to the development of a functioning cotyledonary pla- centa is to support rapid embryonic development and concep- tus growth.40 Thus, the uterine environment is a critical regulator in pregnancy success or failure. Prior to conceptus attachment to the luminal epithelium, the conceptus relies on endometrial secretions, also called histotroph, to support cell proliferation, migration and the morphological changes that occur during elongation.41 Perturbing the native uterine histotroph composi- tion by flushing the uterine lumen with saline on days 4 or 7 after estrus reduced pregnancy per embryo transfer by 33.1 and 30.6%, respectively.42 This evidence is supported by ovine mod- els of uterine gland ablation, whereby histotroph composition is dramatically altered, and hatched blastocysts are unable to undergo elongation.43 Furthermore, machine learning has been utilized to integrate the endometrial transcriptome 7 days after estrus with pregnancy outcomes to predict genes linked to uter- ine receptivity.44 In this discriminate analysis, 50 genes were identified and could predict uterine receptivity with an overall accuracy of 96.1%, regardless of the breed of the animal.44 Therefore, inadequate transcription or secretion of necessary factors within the uterus can contribute to pregnancy loss. Coincidentally, identifying secreted factors within the uterine lumen that are critical for embryonic development presents an opportunity to improve pregnancy outcomes and mitigate pregnancy losses. Failure to respond to conceptus-derived signals and maintain the corpus luteum As previously mentioned, the bovine conceptus begins to secrete IFNT around day 16, and this type 1 interferon elicits robust responses in the endometrium, ultimately extending the life of the corpus luteum. The signaling actions of IFNT are perpetuated in a paracrine manner are reviewed.45 Evidence from sheep has demonstrated that IFNT signals via the inter- feron alpha and beta receptors on luminal endometrial epi- thelial cells to inhibit expression of ESR1 and OXTR, ultimately diminishing the pulsatile release of endometrial PGF2α. 45,46 Thus, the ability of the endometrium to respond to IFNT is critical to successful maternal recognition of pregnancy and maintenance of the corpus luteum. Recent work in dairy heif- ers has revealed that the endometrial responsiveness to IFNT is variable among individuals, and this variability is associated with subsequent fertility.47 After intrauterine infusion of recombinant IFNT, the endometrial transcriptome had differ- ences in expression between heifers classified as highly fertile and subfertile and these genes were associated with cell signal- ing, metabolism, attachment, migration, and extracellular matrix proteins.47 Further, subfertile heifers had lower concen- trations of glycerol and oxylipins derived from arachidonic acid within uterine luminal fluid after IFNT infusion.47 Together, this work indicated that individual animals may have differential responsiveness to IFNT signaling. In the con- text of pregnancy loss, identifying regulators of IFNT sensitiv- ity present an opportunity to improve fertility outcomes, and although the secretion of IFNT is dependent on the embryo, it is worthy of considering if the endometrium has a threshold of sensitivity to various doses of IFNT that is sufficient to elicit a signaling response. Roles of aberrant maternal prostaglandins in pregnancy loss Prostaglandins are lipid-based signaling molecules that have essential roles in regulating bodily processes. Prostaglandins are synthesized from arachidonic acid, and the synthesis of various prostaglandins is mediated by the cyclooxygenase (COX) family of proteins. In cattle, prostaglandins (F2α and E2) begin a definitive increase between days 31-35 of pregnancy and increases in the concentrations of these hormones have been positively correlated with pregnancy.48,49 The expression of PTGS2 (COX2) is upregulated during ovine implantation and is directly related to the degree of invasion of the tropho- blast cells.50 Furthermore, PTGS2 in the mouse model had upregulated during placental development and is therefore involved in decidualization and angiogenesis, promoting pla- cental development.51 As mentioned above, estrus cyclicity in Figure 2. Relationship between peripheral PAG and embryonic survival: A. Cows with lower concentrations of plasma PAG on day 28 of pregnancy experience higher pregnancy loss compared to cows that maintained pregnancy (adapted11); B. Cows experiencing embryonic mortality have lower concentrations of plasma PAG on day 30 of pregnancy compared to cows with embryonic survival (adapted38). http://dx.doi.org/10.58292/CT.v17.11037 6 Citation: Clinical Theriogenology 2025, 17, 11037, http://dx.doi.org/10.58292/CT.v17.11037 cattle is highly dependent on appropriate secretion and regu- lation of prostaglandins from the endometrium. Indeed, during the maternal recognition period, the ablation of PGF2α pulses is necessary for the maintenance and prolonged lifes- pan of the corpus luteum; however, during normal cyclic sce- narios in the absence of a conceptus, prostaglandin will reach the corpus luteum and initiate luteal regression. Although PGF2α is of critical importance to maintain normal cyclicity, the exact roles of PGF2α during placentation are unknown. The conceptus begins to synthesize and secrete prostaglandins around day 13 of pregnancy, eliciting changes to endometrial gene expression.31 Further, circulating PGF2α concentrations increased during days 31-35 in beef cows that maintained pregnancy compared to cows that underwent embryonic mor- tality.48 This period of pregnancy corresponds to the period of active placentation, suggesting that PGF2α may be necessary in facilitating proper attachment of the bovine embryo. Indeed, placental cells are under strict hormonal control; therefore, these hormones tightly regulate the abundance and activity of proteins involved in extracellular matrix remodeling at the placental-endometrial interface.52 Treating caruncular epithe- lial cells isolated from pregnant cows with PGF2α increased cell viability and adhesion.52 Therefore it is likely that appropriate secretion of prostaglandins from either the conceptus and/or endometrium are required to facilitate early placentation events. Further, bovine endometrial cells treated in vitro with indomethacin and aspirin (prostaglandin inhibitors), experi- enced decreases in cell proliferation and cell viability.53 Collectively, it is becoming more apparent that prostaglandins are having a critical role in facilitating dialogue between the conceptus and endometrium, having a role in placentation events such as extracellular matrix remodeling and adhesion, and therefore may be targets for improving pregnancy loss. There are still many unknowns regarding the maternal contri- bution to pregnancy loss in cattle. Likewise, there are consis- tently novel findings published relating to the structure and establishment of the bovine placenta, the dynamic endocrine milieu of pregnancy, and the delicate cell-cell interactions at the placental-endometrial interface that will aid in the under- standing of the mechanisms leading to late embryonic/fetal loss in bovine. A proposed model of key maternal factors con- tributing to pregnancy failure is depicted in Figure 3. Paternal contributions to pregnancy loss Although the sire is traditionally speculated to only contribute half of the genetic material to the oocyte during fertilization, this line of thinking is rapidly challenged as more information pertaining to paternal contributions to pregnancy are revealed. Further, although research regarding pregnancy loss has mainly focused on maternal and embryonic contributions, there is considerable variation in pregnancy loss among sires.54–57 Consequently, variation in genetic indices to mea- sure sire fertility have been developed and rapidly utilized in dairy bulls; however, genomic-based tools have been less uti- lized in beef herds because of the lack of data and validation of quantitative trait loci.58,59 Consequently, sire phenotypic data have been utilized to make associations with fertility. Indeed, associations among bull libido, scrotal circumference, backfat thickness, testis weight, semen quality parameters and sire residual feed intake have all been linked with variation in reproductive function.60,61 Given that genetic selection param- eters for beef bull fertility are limiting, other avenues have been explored to evaluate sire fertility and predict sires that will support embryonic development. Although poor sperm morphometric parameters are useful for chute-side breeding soundness exams to quickly rule out unacceptable bulls, other more quantitative measurements are utilized to improve sire fertility. Computer assisted sperm analysis (CASA) monitors sperm movement and applies algo- rithms to the behavior of sperm cells to estimate sperm cell morphokinetic defects in real time62; CASA is used to predict beef bull fertility in timed AI systems.63 Compared to other Figure 3. Conceptual model of maternal factors contributing to pregnancy failure. Perturbations in luminal histotroph composi- tion, variance in the endometrial response to interferon-tau, and altered prostaglandin metabolism may all contribute to preg- nancy failure at various stages of pregnancy. Identifying key regulators of embryonic survival during milestones of pregnancy will permit a deeper understanding of pregnancy loss. http://dx.doi.org/10.58292/CT.v17.11037 Citation: Clinical Theriogenology 2025, 17, 11037, http://dx.doi.org/10.58292/CT.v17.11037 7 various qualitative measurements assessed in the study, CASA had the greatest coefficient of determination for fertility.63 This study also generated a composite model by incorporating CASA data with image-based flow cytometric analyses, and together these 2 metrics were successful in predicting bull fer- tility.63 One recent study classified 2 groups of bulls as high or low fertility sires and attempted to objectively measure sperm quality.64 One promising method was the detection of aggre- somes located in the head of the sperm. Aggresomes are a buildup of unwanted proteins that occur after a failure in pro- tein modification and are associated with cell death.64 Interestingly, low fertility sires had a significantly higher amount of aggresomes located in the head of the sperm cell (via fluorescent microscopy) prior to a gradient purification commonly used for in vitro fertilization, but this difference between fertility groups disappeared after purification.64 Further study of aggresome defects identified that the low fer- tility sires had a much higher percentage of aggresome defects via image-based flow cytometry.64 Collectively, new molecular insights are developed to quantitatively evaluate sperm cell dynamics and integrate these data into predictive indices inde- pendent of paternal genomics. Advancing sperm cell diagnos- tic and predictive abilities will work in part to reduce pregnancy failure by minimizing errors attributed to inherent sperm defects. As mentioned above, indices such as sire conception rate (SCR) (defined as the probability of a single straw of semen to yield a pregnancy as compared to the means of other bulls in the population) have been developed and are heavily utilized as proxies to estimate sire fertility.65 Despite these indices, the relationship between estimated sire fertility and the paternal contributions to pregnancy failure has remained elusive. One study utilized 10 sires classified as either high or low SCR for in vitro and in vivo embryo production; low SCR sires pro- duced fewer blastocysts compared to high SCR.66 After super- ovulation, low SCR sires produced a higher percentage of unfertilized oocytes and degenerated embryos than high SCR sires.66 Together, these data indicated that low SCR sires may have altered ability to fertilize oocytes and support early embryonic development, ultimately reducing pregnancy establishment. Although the relationship between SCR and the ability of the sire to support embryonic development during early preg- nancy is interesting, a further point should be highlighted. In these studies, there are presumed no differences in sperm cell morphology and motility such that the sperm utilized between high and low fertility bulls would pass routine screening examinations, indicating that differences at the molecular level may be facilitating the reduced ability to support embry- onic development. Research into the molecular contributions and alterations of sperm to embryonic development will per- mit more robust fertility screening types and minimize the proportion of early embryonic failure as a result of improper paternal factors. Sire contributions to placentation One of the proposed reasons why individual sires have vari- able incidence of pregnancy loss is the possibility of variation in the paternal contributions to placentation during the late embryonic period of development. In this hypothesis, it is proposed that differences in PAG expression or transmission of PAG to maternal circulation (via placental vasculature) may be a major component behind the variation in pregnancy losses amongst sires. Indeed, pregnancies sired by some sires consistently yielded higher peripheral concentrations of PAG and experienced lower percentages of pregnancy loss com- pared to pregnancies generated by sires yielding lower concen- trations of PAG (Figure 4).11,37,56,67 Given that complete and successful placentation is required for the continuation of pregnancy to term, one of the tools utilized to further understand the contributions of the sire in successful pregnancy and placentation is the use of uniparen- tal embryos. Parthenogenic (PA) embryos are embryos that contain only the maternal genome and are therefore lacking the entire paternal genome.68 Seminal experiments conducted in mice demonstrated that zygotes generated using 2 male pronuclei yielded poorly developed embryos with normally developing trophoblast, whereas zygotes produced with 2 female pronuclei generate relatively normal embryos, but poor extraembryonic tissue.69,70 Previous studies in cattle have suggested that the sire may be one of the primary contributing factors to a fully developed and functioning placenta.56,71 Some evidence indicated that although PA embryos are capa- ble of survival past the period of maternal recognition of preg- nancy, the transfer of a single PA embryo on day 8 after estrus failed to increase ISG15 expression in peripheral granulocytes compared to an in vivo-produced embryo.72 Further, the trans- fer of multiple PA was sufficient to increase uterine IFNT pro- tein concentrations, indicating that PA embryos are capable of transcribing and translating the signal required to extend the estrous cycle.72 Despite the ability of PA embryos to extend the estrous cycle, the role of the sire in specific aspects of placenta- tion requires further research. Collectively these data strongly suggest that sires have critical roles in pregnancy that expand beyond fertilization but also that unknown sire factors are required for complete and successful attachment, implanta- tion, and overall placentation. Environmental contributions to pregnancy loss There is a close relationship between environmental expo- sures and reproductive success in cattle. Some of the factors that have garnered the most attention in beef cattle reproduc- tive physiology are the interactions of pregnancy and nutri- tional status, exposure to elevated environmental temperatures, Figure 4. Relationship between sire and PAG concentrations in maternal circulation; sires classified as low embryonic loss have higher PAG concentrations compared to sires classified as high embryonic loss (adapted37). http://dx.doi.org/10.58292/CT.v17.11037 8 Citation: Clinical Theriogenology 2025, 17, 11037, http://dx.doi.org/10.58292/CT.v17.11037 and disease. These factors have drawn attention because of the negative relationship with fertility. Although many of the studies investigating the relationship between nutritional status and fertility have been conducted in dairy cattle, beef cattle also face drastic challenges relating to nutritional availability. Adequate nutrition is critical not only during the periconceptual and postpartum period, but proper management of nutrition for prepubertal heifers can impact lifetime reproductive performance.73,74 Indeed, nutri- tional requirements are influenced by cow’s breed, season, and parity, but are also dynamic depending on the physiolog- ical status of the cow. For example, nutrient requirements increase as pregnancy progresses.75 The importance of avail- able nutrients is evident through experiments in cows with a lower body condition score (BCS) had lower pregnancy rates after AI.76 This relationship is due to the imbalance between the hypothalamic-gonadal axis, whereby cows with lower BCS did not return to appropriate cyclicity.73 Cows supplemented with 100 or 150% of their energy and protein requirement during the third trimester of pregnancy had faster ovarian fol- licular growth and more ovulatory follicles 21 days postpar- tum compared to cows maintained on pasture.77 This change in ovulatory capacity directly related to increased pregnancy rates in cows fed 150% of their energy and protein require- ment, ultimately increasing offspring sale value.77 Although fertility increases in supplemented cows, it must be noted that over supplementation of nutrients can also yield negative effects on fertility. For example, cows with elevated BCS (obese) had lower pregnancy rates after embryo transfer, and lower blastocyst rates after superstimulation compared to cows with a moderate BCS.24,25 These data provide strong evi- dence that metabolic status and nutrient supply are 2 factors that require close management for optimal reproductive efficiency. Approximately 70% of the world’s cattle population are in locations considered tropical or subtropical. Reproductive processes are in cattle are sensitive to hyperthermic condi- tion.78 Indeed, heat stress is attributed to reduced estrous behavior, impaired follicular development, reduced oocyte competence, and inhibited embryonic development.78 Therefore, cattle that are well adapted to these environments are necessary to remain efficient and sustainable. For example, oocytes collected from Nelore (Bos indicus) cows were more tolerant of artificial heat stress compared to Jersey and Angus (Bos taurus) cows.79 This was evident by Nelore-derived embryos having higher blastocyst production, higher expres- sion of cell division markers, and lower expression of apop- totic markers when compared to Bos taurus-derived embryos79; furthermore, there was a tendency for Angus-derived embryos to yield fewer pregnancies compared to Nelore embryos.79 Another source of environmental influence of pregnancy loss is the role of infectious diseases in populations of cattle. Although infectious agents can hinder embryonic development, the most pronounced and costly period of abortion occurs between 42 and 260 days. Recent reviews identified the most common infectious agents associated with abortion in cattle and revealed that Neospora caninum, Trueperella pyogenes, bovine viral diar- rhea virus, infectious bovine rhinotracheitis, Leptospira species and fungal infections are the most diagnosed abortive agents Figure 5. Schematic of critical factors contributing to pregnancy success and failure. Pregnancy loss is multifactorial, and the inci- dence of pregnancy failure changes depending on the timepoint of pregnancy. There are specific temporal failures that contribute collectively to pregnancy loss, and reducing these losses at each point will contribute to higher reproductive efficiency and sustain- ability of beef production. http://dx.doi.org/10.58292/CT.v17.11037 Citation: Clinical Theriogenology 2025, 17, 11037, http://dx.doi.org/10.58292/CT.v17.11037 9 identified in beef cattle.80,81 The best management practices to mitigate the impacts of disease-induced abortion are to prevent transmission via rapid diagnostics, maintaining strong biosecu- rity practices, and appropriate management of positive cattle. Monitoring and reducing the incidence of infectious diseases in cattle populations will aid in minimizing pregnancy loss. Conclusion Pregnancy success is highly dependent on numerous condi- tions, and therefore, the etiology of pregnancy loss is multifac- torial. A schematic of critical factors contributing to pregnancy success and failure is depicted in Figure 5. The maternal con- tribution to pregnancy begins well before the period of fertil- ization, whereby complete maturation and final development of the oocyte must be completed. From here on, the maternal endocrine milieu must be conducive for ovulation and rapid reprogramming of ovarian function to prepare for pregnancy. Indeed, the changes to the uterine luminal environment are likely driven by changes to circulating ovarian steroids, and these changes are paramount for supporting the earliest phases of embryonic development. Shortly afterwards, a sym- biosis must occur where the embryonic and maternal systems must work together in concert through cell signaling and pro- liferation to allow for complete attachment and placentation. Although the maternal and embryonic physiological systems are typically center stage in the discussion of pregnancy loss, the roles of the paternal contribution to pregnancy loss are rapidly discovered. 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