Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Animal models of postpartum hemorrhage

Abstract

Postpartum hemorrhage (PPH)—heavy bleeding following childbirth—is a leading cause of morbidity and mortality worldwide. PPH can affect individuals regardless of risks factors and its incidence has been increasing in high-income countries including the United States. The high incidence and severity of this childbirth complication has propelled research into advanced treatments and alternative solutions for patients facing PPH; however, the development of novel treatments is limited by the absence of a common, well-established and well-validated animal model of PPH. A variety of animals have been used for in vivo studies of novel therapeutic materials; however, each of these animals differs considerably from the anatomy and physiology of a postpartum woman, and the methods used for achieving a postpartum hemorrhagic condition vary widely. Here we critically evaluate the various animal models of PPH presented in the literature and propose additional and alternative methods for modeling PPH in in vivo studies. We highlight how current animal models successfully or unsuccessfully mimic the anatomy and physiology of a postpartum woman and how this may impact treatment development. We aim to equip researchers with the necessary background information to select appropriate animal models for their research related to PPH solutions, while supporting the goals of refinement, reduction and replacement (3Rs) in preclinical animal studies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: PPH causes and occurrence.
Fig. 2: Uterine anatomy and vasculature.
Fig. 3: Animal models of PPH.
Fig. 4: Methods for inducing PPH.

Similar content being viewed by others

References

  1. Wormer, K. C., Jamil, R. & Bryant, S. Acute postpartum hemorrhage. StatPearls [Internet] https://www.ncbi.nlm.nih.gov/books/NBK499988/ (updated 8 May 2023).

  2. Rossen, J., Okland, I., Nilsen, O. B. & Eggebo, T. M. Is there an increase of postpartum hemorrhage, and is severe hemorrhage associated with more frequent use of obstetric interventions? Acta Obstet. Gynecol. Scand. 89, 1248–1255 (2010).

    Article  PubMed  Google Scholar 

  3. Schoretsanitis, G. et al. Postpartum hemorrhage and postpartum depression: a systematic review and meta-analysis of observational studies. Acta Psychiatr. Scand. https://doi.org/10.1111/acps.13583 (2023).

    Article  PubMed  Google Scholar 

  4. Abrams, E. T. & Rutherford, J. N. Framing postpartum hemorrhage as a consequence of human placental biology: an evolutionary and comparative perspective. Am. Anthropol. 113, 417–430 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Evensen, A., Anderson, J. M. & Fontaine, P. Postpartum hemorrhage: prevention and treatment. Am. Fam. Physician 95, 442–449 (2017).

    PubMed  Google Scholar 

  6. Chainarong, N., Deevongkij, K. & Petpichetchian, C. Secondary postpartum hemorrhage: Incidence, etiologies, and clinical courses in the setting of a high cesarean delivery rate. PLoS ONE 17, e0264583 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Reale, S. C., Easter, S. R., Xu, X., Bateman, B. T. & Farber, M. K. Trends in postpartum hemorrhage in the United States from 2010 to 2014. Anesth. Analg. 130, e119–e122 (2020).

    Article  PubMed  Google Scholar 

  8. Lindquist, J. D. & Vogelzang, R. L. Pelvic artery embolization for treatment of postpartum hemorrhage. Semin. Intervent. Radiol. 35, 41–47 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Weeks, A. The prevention and treatment of postpartum haemorrhage: what do we know, and where do we go to next? BJOG 122, 202–210 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. van Steijn, M. E. et al. Severe postpartum hemorrhage increases risk of posttraumatic stress disorder: a prospective cohort study. J. Psychosom. Obstet. Gynaecol. 42, 335–345 (2021).

    Article  PubMed  Google Scholar 

  11. Mansukhani, R. et al. Maternal anaemia and the risk of postpartum haemorrhage: a cohort analysis of data from the WOMAN-2 trial. Lancet Glob. Health 11, e1249–e1259 (2023).

    Article  Google Scholar 

  12. Jonard, M. et al. Postpartum acute renal failure: a multicenter study of risk factors in patients admitted to ICU. Ann. Intensive Care https://doi.org/10.1186/s13613-014-0036-6 (2014).

  13. Erez, O. et al. DIC in pregnancy—pathophysiology, clinical characteristics, diagnostic scores, and treatments. J. Blood Med. 13, 21–44 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bienstock, J. L., Eke, A. C. & Hueppchen, N. A. Postpartum hemorrhage. N. Engl. J. Med. 384, 1635–1645 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rath, W. H. Postpartum hemorrhage—update on problems of definitions and diagnosis. Acta Obstet. Gynecol. Scand. 90, 421–428 (2011).

    Article  PubMed  Google Scholar 

  16. Gibbins, K. J., Albright, C. M. & Rouse, D. J. Postpartum hemorrhage in the developed world: whither misoprostol? Am. J. Obstet. Gynecol. 208, 181–183 (2013).

    Article  PubMed  Google Scholar 

  17. Ahmadzia, H. K., Grotegut, C. A. & James, A. H. A national update on rates of postpartum haemorrhage and related interventions. Blood Transfus. 18, 247–253 (2020).

    PubMed  PubMed Central  Google Scholar 

  18. Cunningham, C. et al. PPH Butterfly: a novel device to treat postpartum haemorrhage through uterine compression. BMJ Innov. 3, 45–54 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Escobar, M. F. et al. FIGO recommendations on the management of postpartum hemorrhage 2022. Int. J. Gynaecol. Obstet. 157, 3–50 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bakri, Y., B-Lynch, C. & Alouini, S. Second generation of intrauterine balloon tamponade: new perspective. BMJ Innov. 6, 1–3 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Rani, P. R. & Begum, J. Recent advances in the management of major postpartum haemorrhage—a review. J. Clin. Diagn. Res. 11, QE01–QE05 (2017).

    PubMed  PubMed Central  Google Scholar 

  22. Chen, Y. et al. Prostaglandins for postpartum hemorrhage: pharmacology, application, and current opinion. Pharmacology 106, 477–487 (2021).

    Article  CAS  PubMed  Google Scholar 

  23. Ricciotti, E. & FitzGerald, G. A. Prostaglandins and inflammation. Arterioscler. Thromb. Vasc. Biol. 31, 986–1000 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Coulange, L. et al. Uterine necrosis following selective embolization for postpartum hemorrhage using absorbable material. Acta Obstet. Gynecol. Scand. 88, 238–240 (2009).

    Article  PubMed  Google Scholar 

  25. Kim, G. M., Yoon, C. J., Seong, N. J., Kang, S. G. & Kim, Y. J. Postpartum haemorrhage from ruptured pseudoaneurysm: efficacy of transcatheter arterial embolisation using N-butyl-2-cyanoacrylate. Eur. Radiol. 23, 2344–2349 (2013).

    Article  PubMed  Google Scholar 

  26. Kim, J.-E. et al. Postpartum hemorrhage from non-uterine arteries: clinical importance of their detection and the results of selective embolization. Acta Radiol. 59, 932–938 (2018).

    Article  PubMed  Google Scholar 

  27. Ngwenya, S. Postpartum hemorrhage: incidence, risk factors, and outcomes in a low-resource setting. Int. J. Womens Health 8, 647–650 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  28. McKenney, K., Lundsberg, L. S., Culhane, J. F., Partridge, C. & Son, M. Factors associated with hysterectomy for postpartum hemorrhage: a case–control study. Am. J. Obstet. Gynecol. https://doi.org/10.1016/j.ajog.2021.11.750 (2022).

  29. Zhang, Y. et al. Emergency obstetric hysterectomy for life-threatening postpartum hemorrhage: a 12-year review. Medicine 96, e8443 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Rodriguez, M. I. et al. A novel tamponade agent for management of post partum hemorrhage: adaptation of the Xstat mini-sponge applicator for obstetric use. BMC Pregnancy Childbirth 17, 187 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Doodnaught, G. M., O’Toole, E. & Pang, D. S. J. Management of a severe peripartum hemorrhage following cesarean section in a dog. Can. Vet. J. 61, 589–594 (2020).

    PubMed  PubMed Central  Google Scholar 

  32. Rees, G. Postpartum emergencies in cows. In Pract. 38, 23–31 (2016).

    Article  Google Scholar 

  33. Arnold, C. E., Payne, M., Thompson, J. A. & Slovis, N. M. Periparturient hemorrhage in mares: 73 cases (1998–2005). J. Am. Vet. Med. Assoc. 232, 1345–1351 (2008).

    Article  PubMed  Google Scholar 

  34. Dolente, B. A., Sullivan, E. K., Boston, R. & Johnston, J. K. Mares admitted to a referral hospital for postpartum emergencies: 163 cases (1992–2002). J. Vet. Emerg. Crit. Care 15, 193–200 (2005).

    Article  Google Scholar 

  35. Pijnenborg, R., Vercruysse, L. & Hanssens, M. The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 27, 939–958 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Nizard, J., Pessel, M., De Keersmaecker, B., Barbet, J. P. & Ville, Y. High-intensity focused ultrasound in the treatment of postpartum hemorrhage: an animal model. Ultrasound Obstet. Gynecol. 23, 262–266 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Malik, M., Roh, M. & England, S. K. Uterine contractions in rodent models and humans. Acta Physiol. 231, e13607 (2021).

    Article  CAS  Google Scholar 

  38. Ishibashi, H. et al. Resuscitative efficacy of hemoglobin vesicles for severe postpartum hemorrhage in pregnant rabbits. Sci. Rep. 11, 22367 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Burton, G. J., Woods, A. W., Jauniaux, E. & Kingdom, J. C. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta 30, 473–482 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chaudhry, R. & Chaudhry, K. Anatomy, abdomen and pelvis: uterus round ligament. StatPearls [Internet] https://www.ncbi.nlm.nih.gov/books/NBK499970/ (updated 24 July 2023).

  41. Hwuang, E. et al. Assessment of uterine artery geometry and hemodynamics in human pregnancy with 4D flow MRI and its correlation with Doppler ultrasound. J. Magn. Reson. Imaging 49, 59–68 (2019).

    Article  PubMed  Google Scholar 

  42. Ameer, M. A., Fagan, S. E., Sosa-Stanley, J. N. & Peterson, D. C. Anatomy, abdomen and pelvis: uterus. StatPearls [Internet] https://www.ncbi.nlm.nih.gov/books/NBK470297/ (updated 6 December 2022).

  43. Gill, P., Patel, A. & Van Hook, J. W. Uterine atony. StatPearls [Internet] https://www.ncbi.nlm.nih.gov/books/NBK493238/ (updated 4 July 2023).

  44. Paliulyte, V. et al. Physiological uterine involution in primiparous and multiparous women: ultrasound study. Obstet. Gynecol. Int. 2017, 6739345 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Triantafyllidou, O., Kastora, S., Messini, I. & Kalampokis, D. Subinvolution of the placental site as the cause of hysterectomy in young woman. BMJ Case Rep. https://doi.org/10.1136/bcr-2020-238945 (2021).

  46. Whitley, G. S. & Cartwright, J. E. Trophoblast-mediated spiral artery remodelling: a role for apoptosis. J. Anat. 215, 21–26 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ferguson, J. E., Bourgeois, F. J. & Underwood, P. B. B-Lynch suture for postpartum hemorrhage. Obstet. Gynecol. 95, 1020–1022 (2000).

    CAS  PubMed  Google Scholar 

  48. Myers, K. M. & Elad, D. Biomechanics of the human uterus. Wiley Interdiscip. Rev. Syst. Biol. Med. https://doi.org/10.1002/wsbm.1388 (2017).

  49. Habiba, M., Heyn, R., Bianchi, P., Brosens, I. & Benagiano, G. The development of the human uterus: morphogenesis to menarche. Hum. Reprod. Update 27, 1–26 (2021).

    Article  CAS  PubMed  Google Scholar 

  50. Figueira, P., Abrão, M., Krikun, G. & Taylor, H. Stem cells in endometrium and their role in the pathogenesis of endometriosis. Ann. N. Y. Acad. Sci. 1221, 10–17 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Deligdisch, L. Hormonal pathology of the endometrium. Mod. Pathol. 13, 285–294 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Weiss, S. et al. Three-dimensional fiber architecture of the nonpregnant human uterus determined ex vivo using magnetic resonance diffusion tensor imaging. Anat. Rec. A 288, 84–90 (2006).

    Article  Google Scholar 

  53. Dunford, J., L, E., Atia, J., Blanks, A. & van den Berg, H. Computational physiology of uterine smooth muscle. Sci. Prog. 102, 103–126 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Kota, S. K. et al. Endocrinology of parturition. Indian J. Endocrinol. Metab. 17, 50–59 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  55. DeMayo, F. J., Zhao, B., Takamoto, N. & Tsai, S. Y. Mechanisms of action of estrogen and progesterone. Ann. N. Y. Acad. Sci. 955, 48–59 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Fuentes, N. & Silveyra, P. Estrogen receptor signaling mechanisms. Adv. Protein Chem. Struct. Biol. 116, 135–170 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yu, K. et al. Estrogen receptor function: impact on the human endometrium. Front. Endocrinol. 13, 827724 (2022).

    Article  Google Scholar 

  58. Taraborrelli, S. Physiology, production and action of progesterone. Acta Obstet. Gynecol. Scand. 94, 8–16 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Norman, J. E. Progesterone and preterm birth. Int. J. Gynaecol. Obstet. 150, 24–30 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Patel, B. et al. Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Hum. Reprod. Update 21, 155–173 (2015).

    Article  CAS  PubMed  Google Scholar 

  61. Zakar, T. & Hertelendy, F. Progesterone withdrawal: key to parturition. Am. J. Obstet. Gynecol. 196, 289–296 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Peavey, M. C. et al. Progesterone receptor isoform B regulates the Oxtr–Plcl2–Trpc3 pathway to suppress uterine contractility. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2011643118 (2021).

  63. Ku, C. W. et al. Serum progesterone distribution in normal pregnancies compared to pregnancies complicated by threatened miscarriage from 5 to 13 weeks gestation: a prospective cohort study. BMC Pregnancy Childbirth 18, 360 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ranisavljevic, N. et al. Low luteal serum progesterone levels are associated with lower ongoing pregnancy and live birth rates in ART: systematic review and meta-analyses. Front. Endocrinol. 13, 892753 (2022).

    Article  Google Scholar 

  65. Barrett, J. & Wathes, D. C. The effect of oxytocin on progesterone secretion and of PGF2 on oxytocin secretion from bovine luteal and granulosa cells in culture. Anim. Reprod. Sci. 22, 297–309 (1990).

    Article  CAS  Google Scholar 

  66. Vrachnis, N., Malamas, F. M., Sifakis, S., Deligeoroglou, E. & Iliodromiti, Z. The oxytocin–oxytocin receptor system and its antagonists as tocolytic agents. Int. J. Endocrinol. 2011, 350546 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Fuchs, A. R., Fuchs, F., Husslein, P. & Soloff, M. S. Oxytocin receptors in the human uterus during pregnancy and parturition. Am. J. Obstet. Gynecol. 150, 734–741 (1984).

    Article  CAS  PubMed  Google Scholar 

  68. Maggi, M. et al. Human myometrium during pregnancy contains and responds to V1 vasopressin receptors as well as oxytocin receptors. J. Clin. Endocrinol. Metab. 70, 1142–1154 (1990).

    Article  CAS  PubMed  Google Scholar 

  69. Mergenthaler, P. & Meisel, A. in Principles of Translational Science in Medicine 83–90 (Academic Press, 2015).

  70. Sprott, R. L. in Studies of Aging Vol. 1 (eds Sternberg, H. & Timiras, P. S.) Ch. 8, 208 (Springer, 1999).

  71. Davidson, M. K., Lindsey, J. R. & Davis, J. K. Requirements and selection of an animal model. Isr. J. Med. Sci. 23, 551–555 (1987).

    CAS  PubMed  Google Scholar 

  72. Product Development under the Animal Rule: Guidance for Industry (FDA & DHHS, 2015).

  73. Lutton, E. J., Lammers, W., James, S., van den Berg, H. A. & Blanks, A. M. Identification of uterine pacemaker regions at the myometrial-placental interface in the rat. J. Physiol. 596, 2841–2852 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Zeng, R. et al. Prostaglandin F evokes vasoconstrictor and vasodepressor activities that are both independent of the F prostanoid receptor. FASEB J. 36, e22293 (2022).

    Article  CAS  PubMed  Google Scholar 

  75. Milewski, M. et al. Rapid absorption of dry-powder intranasal oxytocin. Pharm. Res. 33, 1936–1944 (2016).

    Article  CAS  PubMed  Google Scholar 

  76. Zhu, C., Estrada, M., White, J. & Lal, M. Heat-stable sublingual oxytocin tablets as a potential needle-free approach for preventing postpartum hemorrhage in low-resource settings. Drug Deliv. Transl. Res. 8, 853–856 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Warner, R. et al. Comparative pharmacokinetics of meloxicam between healthy post-partum vs. mid-lactation dairy cattle. Front. Vet. Sci. 7, 548 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Hakomaki, H. et al. Pharmacokinetics of buprenorphine in pregnant sheep after intravenous injection. Pharmacol. Res. Perspect. 9, e00726 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Fritz, B. R. et al. Determination of milk concentrations and pharmacokinetics of salicylic acid following acetylsalicylic acid (aspirin) administration in postpartum dairy cows. J. Dairy Sci. 105, 9869–9881 (2022).

    Article  CAS  PubMed  Google Scholar 

  80. Chaphekar, N., Dodeja, P., Shaik, I. H., Caritis, S. & Venkataramanan, R. Maternal–fetal pharmacology of drugs: a review of current status of the application of physiologically based pharmacokinetic models. Front. Pediatr. 9, 733823 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Fernandez, H., Hafiz, A., Khrouf, M., Morel, O. & Chavatte-Palmer, P. Evaluation of the rabbit as an experimental model for human uterine synechia. J. Hum. Reprod. Sci. https://doi.org/10.4103/0974-1208.101017 (2012).

  82. Boyd, K. M. A., Rendi, M., Garcia, R. & Gibson-Corley, K. in Comparative Anatomy and Physiology. 2 edn, Ch. 17 303–334 (Academic Press, 2018).

  83. Fischer, B., Chavatte-Palmer, P., Viebahn, C., Navarrete Santos, A. & Duranthon, V. Rabbit as a reproductive model for human health. Reproduction 144, 1–10 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Furukawa, S., Kuroda, Y. & Sugiyama, A. A comparison of the histological structure of the placenta in experimental animals. J. Toxicol. Pathol. 27, 11–18 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Faber, J. J. & Hart, F. M. The rabbit placenta as an organ of diffusional exchange: comparison with other species by dimensional analysis. Circ. Res. 19, 816–833 (1966).

    Article  CAS  PubMed  Google Scholar 

  86. Kaufmann, P. & Davidoff, M. The Guinea-Pig Placenta (Springer, 1977).

  87. Harrell, M. I. et al. Exploring the pregnant guinea pig as a model for group B Streptococcus intrauterine infection. J. Infect. Dis. Med. 2, 109 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Grigsby, P. L. Animal models to study placental development and function throughout normal and dysfunctional human pregnancy. Semin. Reprod. Med. 34, 11–16 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. de Gaisán, E. O. & Aoki, A. Permeability studies of the labyrinth in the guinea pig placenta. I. Perfusion of fixatives and tracers into the fetal circulation. Anat. Embryol. 171, 71–74 (1985).

    Article  Google Scholar 

  90. Morrison, J. L. et al. Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic. J. Physiol. 596, 5535–5569 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wildman, D. E. et al. Spontaneous abortion and preterm labor and delivery in nonhuman primates: evidence from a captive colony of chimpanzees (Pan troglodytes). PLoS ONE 6, e24509 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Institute of Medicine. Preterm Birth: Causes, Consequences, and Prevention (National Academies Press, 2007).

  93. Coan, P. M., Ferguson-Smith, A. C. & Burton, G. J. Developmental dynamics of the definitive mouse placenta assessed by stereology. Biol Reprod. 70, 1806–1813 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Nayak, N. R. & Giudice, L. C. Comparative biology of the IGF system in endometrium, decidua, and placenta, and clinical implications for foetal growth and implantation disorders. Placenta 24, 281–296 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Domestic rabbit (Oryctolagus cuniculus). Comparative Placentation http://placentation.ucsd.edu/rabbitfs.htm (2008).

  96. de Rijk, E. P. C. T. & Van Esch, E. The macaque placenta—a mini-review. Toxicol. Pathol. 36, 108S–118S (2008).

    Article  Google Scholar 

  97. Rinkenberger, J. & Werb, Z. The labyrinthine placenta. Nat. Genet. 25, 248–250 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Furukawa, S., Tsuji, N. & Sugiyama, A. Morphology and physiology of rat placenta for toxicological evaluation. J. Toxicol. Pathol. 32, 1–17 (2019).

    Article  PubMed  Google Scholar 

  99. Mess, A. The guinea pig placenta: model of placental growth dynamics. Placenta 28, 812–815 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Samuel, C. A., Jack, P. & Nathanielsz, P. W. Ultrastructural studies of the rabbit placenta in the last third of gestation. J. Reprod. Fertil. 45, 9–14 (1975).

    Article  CAS  PubMed  Google Scholar 

  101. Li, C. et al. The IGF axis in baboon pregnancy: placental and systemic responses to feeding 70% global ad libitum diet. Placenta 28, 1200–1210 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Carter, A. M. & Enders, A. C. Comparative aspects of trophoblast development and placentation. Reprod. Biol. Endocrinol. 2, 46 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Carter, A. M. Unique aspects of human placentation. Int. J. Mol. Sci. https://doi.org/10.3390/ijms22158099 (2021).

  104. Soares, M. J., Chakraborty, D., Karim Rumi, M. A., Konno, T. & Renaud, S. J. Rat placentation: an experimental model for investigating the hemochorial maternal–fetal interface. Placenta 33, 233–243 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Fowden, A. L., Sferruzzi-Perri, A. N., Coan, P. M., Constancia, M. & Burton, G. J. Placental efficiency and adaptation: endocrine regulation. J. Physiol. 587, 3459–3472 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Faber, J., Thornburg, K. & Binder, N. Physiology of placental transfer in mammals. Am. Zool. 32, 343–354 (1992).

    Article  Google Scholar 

  107. E, B. The mighty mouse: the impact of rodents on advances in biomedical research. Sci. Med. 110, 207–211 (2013).

    Google Scholar 

  108. Foote, R. & Carney, E. The rabbit as a model for reproductive and developmental toxicity studies. Reprod. Toxicol. 14, 477–493 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Banata Gang-Ny, A. et al. FairEmbo concept for postpartum hemorrhage: evaluation of the efficacy of suture fragment compared with Gelatin Sponge Torpedo embolization in a post-gravid swine model. J. Pers. Med. https://doi.org/10.3390/jpm13010124 (2023).

  110. Elovitz, M. A. & Mrinalini, C. Animal models of preterm birth. Trends Endocrinol. Metab. 15, 479–487 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Freeman, S. M. & Young, L. J. Comparative perspectives on oxytocin and vasopressin receptor research in rodents and primates: translational implications. J. Neuroendocrinol. https://doi.org/10.1111/jne.12382 (2016).

  112. Stewart, H. J., Stevenson, K. R. & Flint, A. P. Isolation and structure of a partial sheep oxytocin receptor cDNA and its use as a probe for northern analysis of endometrial RNA. J. Mol. Endocrinol. 10, 359–361 (1993).

    Article  CAS  PubMed  Google Scholar 

  113. Jeng, Y. J., Soloff, S. L., Anderson, G. D. & Soloff, M. S. Regulation of oxytocin receptor expression in cultured human myometrial cells by fetal bovine serum and lysophospholipids. Endocrinology 144, 61–68 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Kis, A. et al. Oxytocin receptor gene polymorphisms are associated with human directed social behavior in dogs (Canis familiaris). PLoS ONE 9, e83993 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Balki, M., Cristian, A. L., Kingdom, J. & Carvalho, J. C. Oxytocin pretreatment of pregnant rat myometrium reduces the efficacy of oxytocin but not of ergonovine maleate or prostaglandin F. Reprod. Sci. 17, 269–277 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Hu, C. et al. Prostaglandin D2 evokes potent uterine contraction via the F prostanoid receptor in postpartum rats. Eur. J. Pharmacol. 836, 11–17 (2018).

    Article  CAS  PubMed  Google Scholar 

  117. Balki, M., Kanwal, N., Erik-Soussi, M., Kingdom, J. & Carvalho, J. C. Contractile efficacy of various prostaglandins in pregnant rat myometrium pretreated with oxytocin. Reprod. Sci. 19, 968–975 (2012).

    Article  PubMed  Google Scholar 

  118. Survival Blood Collection in Mice and Rats (NIH Office of Intramural Research ARAC Guidelines, 2022).

  119. Cui, M. et al. Large animal models in the study of gynecological diseases. Front. Cell Dev. Biol. 11, 1110551 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Iwanaga, R. et al. Comparative histology of mouse, rat, and human pelvic ligaments. Int. Urogynecol. J. 27, 1697–1704 (2016).

    Article  PubMed  Google Scholar 

  121. Massri, N., Loia, R., Sones, J. L., Arora, R. & Douglas, N. C. Vascular changes in the cycling and early pregnant uterus. JCI Insight https://doi.org/10.1172/jci.insight.163422 (2023).

  122. Tiemann, T. T. et al. Towards uterus tissue engineering: a comparative study of sheep uterus decellularisation. Mol. Hum. Reprod. 26, 167–178 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zheng, H. H. et al. Identification of canine pyometra-associated metabolites using untargeted metabolomics. Int. J. Mol. Sci. https://doi.org/10.3390/ijms232214161 (2022).

  124. Campo, H. et al. De- and recellularization of the pig uterus: a bioengineering pilot study. Biol. Reprod. 96, 34–45 (2017).

    Article  PubMed  Google Scholar 

  125. Bauer, C. & Harrison, T. Retrospective analysis of the incidence of retained placenta in 3 large colonies of NHP. Comp. Med. 66, 143–149 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Nogalski, Z. & Piwczynski, D. Association of length of pregnancy with other reproductive traits in dairy cattle. Asian-Australas. J. Anim. Sci. 25, 22–27 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Macmillan, K., Kastelic, J. P. & Colazo, M. G. Update on multiple ovulations in dairy cattle. Animals https://doi.org/10.3390/ani8050062 (2018).

  128. Santos, L. C. & Silva, J. F. Molecular factors involved in the reproductive morphophysiology of female domestic cat (Felis catus). Animals https://doi.org/10.3390/ani13193153 (2023).

  129. Carter, A. M. & Enders, A. C. Placentation in mammals: definitive placenta, yolk sac, and paraplacenta. Theriogenology 86, 278–287 (2016).

    Article  CAS  PubMed  Google Scholar 

  130. Leiser, R. & Koob, B. Development and characteristics of placentation in a carnivore, the domestic cat. J. Exp. Zool. 266, 642–656 (1993).

    Article  CAS  PubMed  Google Scholar 

  131. Kowalewski, M. P. et al. Correction to: canine endotheliochorial placenta: morpho-functional aspects. Adv. Anat. Embryol. Cell Biol. 234, C1–C2 (2021).

    Article  PubMed  Google Scholar 

  132. Vilaregut, L., Lores, M. & Wilsher, S. The yolk sac of the equine placenta. Its remnant and potential problems. J. Equine Vet. Sci. 96, 103322 (2021).

    Article  PubMed  Google Scholar 

  133. Sarli, G. et al. Canine placenta histological findings and microvascular density: the histological basis of a negative neonatal outcome? Animals https://doi.org/10.3390/ani11051418 (2021).

  134. Houston, M. L. The development of the baboon (Papio sp.) placenta during the fetal period of gestation. Am. J. Anat. 126, 17–29 (1969).

    Article  CAS  PubMed  Google Scholar 

  135. King, B. Comparative studies of structure and function in mammalian placentas with special reference to maternal–fetal transfer of iron. Am. Zool. 32, 331–342 (1992).

    Article  Google Scholar 

  136. Hafez, S. A., Borowicz, P., Reynolds, L. P. & Redmer, D. A. Maternal and fetal microvasculature in sheep placenta at several stages of gestation. J. Anat. 216, 292–300 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Haeger, J. D., Hambruch., N. & Pfarrer, C. Placental development and its control in cattle. Biosci. Proc. https://doi.org/10.1530/biosciprocs.8.012 (2019).

  138. Leiser, R. et al. Fetal villosity and microvasculature of the bovine placentome in the second half of gestation. J. Anat. 191, 517–527 (1997).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Schmidt, J. K. et al. Placenta-derived macaque trophoblast stem cells: differentiation to syncytiotrophoblasts and extravillous trophoblasts reveals phenotypic reprogramming. Sci. Rep. https://doi.org/10.1038/s41598-020-76313-w (2020).

  140. Robb, V. A., Pepe, G. J. & Albrecht, E. D. Placental villous vascular endothelial growth factor expression and vascularization after estrogen suppression during the last two-thirds of baboon pregnancy. Endocrine 31, 260–267 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Arther, G. H., Noakes, D. E., Parkinson, T. J. & England, G. C. W. in Arthur’s Veterinary Reproduction and Obstetrics 8th edn, Ch. 2 57–68 (Saunders, 2001).

  142. Tamilselvan, S. et al. Gross morphology of placenta in mare. Int. J. Curr. Microbiol. Appl. Sci. 4, 197–200 (2015).

    CAS  Google Scholar 

  143. Carter, A. M. Evolution of placental function in mammals: the molecular basis of gas and nutrient transfer, hormone secretion, and immune responses. Physiol. Rev. 92, 1543–1576 (2012).

    Article  CAS  PubMed  Google Scholar 

  144. Kiso, Y., Yamashita, A., Sasaki, F. & Yamauchi, S. Maternal blood vascular architecture of the dog placenta during the second half of pregnancy. Jpn J. Anim. Reprod. 36, 120–126 (1990).

    Article  Google Scholar 

  145. Gahlenbeck, H., Frerking, H., Rathschlag-Schaefer, A. M. & Bartels, H. Oxygen and carbon dioxide exchange across the cow placenta during the second part of pregnancy. Resp. Physiol. 4, 119–131 (1968).

    Article  CAS  Google Scholar 

  146. Vallet, J., McNeel, A., Miles, J. & Freking, B. Placental accommodations for transport and metabolism during intra-uterine crowding in pigs. J. Anim. Sci. Biotechnol. 5, 55 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Morel, O. et al. Radiofrequency ablation of retained placenta accreta after conservative management: preliminary evaluation in the pregnant ewe and in normal human placenta in vitro. BJOG 116, 915–922 (2009).

    Article  CAS  PubMed  Google Scholar 

  148. Laurent, A., Pelage, J. P., Wassef, M. & Martal, J. Fertility after bilateral uterine artery embolization in a sheep model. Fertil. Steril. 89, 1371–1383 (2008).

    Article  PubMed  Google Scholar 

  149. Balasuriya, H. et al. Primate maternal placental angiography. Placenta 31, 32–36 (2010).

    Article  CAS  PubMed  Google Scholar 

  150. Bauer, C. The baboon (Papio sp.) as a model for female reproduction studies. Contraception 92, 120–123 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Lu, K. G. & Sprayberry, K. A. Managing reproduction emergencies in the field: Part 2: parturient and periparturient conditions. Vet. Clin. North Am. Equine Pract. 37, 367–405 (2021).

    Article  CAS  PubMed  Google Scholar 

  152. Perkins, N. R. & Frazer, G. S. Reproductive emergencies in the mare. Vet. Clin. North Am. Equine Pract. 10, 643–670 (1994).

    Article  CAS  PubMed  Google Scholar 

  153. Sun, P., Xiao, H., Wang, J., Zhang, S. & Cao, X. Pharmacokinetics and bioavailability of carbetocin after intravenous and intramuscular administration in cows and gilts. J. Vet. Pharmacol. Ther. 43, 237–240 (2020).

    Article  CAS  PubMed  Google Scholar 

  154. Raia-Barjat, T. et al. Animal models of chorioamnionitis: considerations for translational medicine. Biomedicines https://doi.org/10.3390/biomedicines10040811 (2022).

  155. Ziegler, A., Gonzalez, L. & Blikslager, A. Large animal models: the key to translational discovery in digestive disease research. Cell Mol. Gastroenterol. Hepatol. 2, 716–724 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Bonney, E. A. Demystifying animal models of adverse pregnancy outcomes: touching bench and bedside. Am. J. Reprod. Immunol. 69, 567–584 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Ypsilantis, P., Deftereos, S., Prassopoulos, P. & Simopoulos, C. Ultrasonographic diagnosis of pregnancy in rats. J. Am. Assoc. Lab. Anim. Sci. 48, 734–739 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Nakamura, T., Fujiwara, K., Saitou, M. & Tsukiyama, T. Non-human primates as a model for human development. Stem Cell Rep. 16, 1093–1103 (2021).

    Article  CAS  Google Scholar 

  159. Felix, S. U. Conception and gestation in domestic animals and various factors influencing them: a review. J. Dairy Vet. Sci. https://doi.org/10.19080/jdvs.2018.05.555656 (2018).

  160. Elsohaby, I. et al. Flock management risk factors associated with Q fever infection in sheep in Saudi Arabia. Animals https://doi.org/10.3390/ani11071948 (2021).

  161. Alvarez-Alonso, R. et al. Monitoring Coxiella burnetii infection in naturally infected dairy sheep flocks throughout four lambing seasons and investigation of viable bacteria. Front. Vet. Sci. 7, 352 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Wang, J., Ding, Y., Jia, Y.-Y. & Zhao, G.-Y. A new Co(II)-coordination polymer: prevention of postpartum hemorrhage by increasing the prothrombin activity. J. Coord. Chem. 73, 3344–3353 (2020).

    Article  CAS  Google Scholar 

  163. Pan, Q., Huang, Y., Dong, Y., Shi, G.-G. & Wang, Y.-H. 3D Cu(II) cluster-based coordination polymer: increasing the activity of prothrombin and preventing postpartum hemorrhage. J. Cluster Sci. 33, 1177–1183 (2021).

    Article  Google Scholar 

  164. Wang, B. et al. Preparation of fibroblast suppressive poly(ethylene glycol)-b-poly(l-phenylalanine)/poly(ethylene glycol) hydrogel and its application in intrauterine fibrosis prevention. ACS Biomater. Sci. Eng. 7, 311–321 (2021).

    Article  CAS  PubMed  Google Scholar 

  165. Liu, J. et al. The effects of increasing aortic occlusion times at the level of the highest renal artery (Zone II) in the normovolemic rabbit model. Acad. Radiol. 29, 986–993 (2022).

    Article  PubMed  Google Scholar 

  166. Yuki, Y. et al. Efficacy of resuscitative infusion with hemoglobin vesicles in rabbits with massive obstetric hemorrhage. Am. J. Obstet. Gynecol. 224, 398 e391–398 e311 (2021).

    Article  Google Scholar 

  167. Xianbao, L., Hong, Z., Xu, Z., Chunfang, Z. & Dunjin, C. Dexmedetomidine reduced cytokine release during postpartum bleeding-induced multiple organ dysfunction syndrome in rats. Mediators Inflamm. 2013, 627831 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Sheng, C. et al. Acute lung inflammatory response and injury after hemorrhagic shock are more severe in postpartum rabbits. Crit. Care Med. 40, 1570–1577 (2012).

    Article  PubMed  Google Scholar 

  169. Yang, X. et al. Dietary beta-carotene on postpartum uterine recovery in mice: crosstalk between gut microbiota and inflammation. Front. Immunol. 12, 744425 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Arbeiter, K. The use of progestins in the treatment of persistent uterine hemorrhage in the postpartum bitch and cow: a clinical report. Theriogenology 4, 11–13 (1975).

    Article  CAS  PubMed  Google Scholar 

  171. Paul, J. W. et al. Drug delivery to the human and mouse uterus using immunoliposomes targeted to the oxytocin receptor. Am. J. Obstet. Gynecol. 216, 283 e281–283 e214 (2017).

    Article  Google Scholar 

  172. Liles, J. H. & Flecknell, P. A. The use of non-steroidal anti-inflammatory drugs for the relief of pain in laboratory rodents and rabbits. Lab. Anim. 26, 241–255 (1992).

    Article  CAS  PubMed  Google Scholar 

  173. Aiken, J. Aspirin and inodmethacin prolong parturition in rats: evidence that prostaglandins contribute to expulsion of foetus. Nature 240, 21–25 (1972).

    Article  CAS  PubMed  Google Scholar 

  174. Kearney, K. J. et al. Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2014810118 (2021).

  175. Senior, J. & Whalley, E. T. The influence of drugs on the kinin-forming system in relation to pregnancy and parturition in the rat. J. Reprod. Fert. 47, 319–323 (1976).

    Article  CAS  Google Scholar 

  176. Yin, Z. et al. Progesterone inhibits contraction and increases TREK-1 potassium channel expression in late pregnant rat uteruses. Oncotarget 9, 651–661 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Pakoussi, T., Mouzou, A. P., Metowogo, K., Aklikokou, K. A. & Gbeassor, M. How do Spondias mombin L (Anacardiaceae) leaves extract increase uterine smooth muscle contractions to facilitate child birth in parturient women? Afr. Health Sci. 18, 235–243 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Li, X. et al. The Th1/Th2/Th17/Treg paradigm induced by stachydrine hydrochloride reduces uterine bleeding in RU486-induced abortion mice. J. Ethnopharmacol. 145, 241–253 (2013).

    Article  CAS  PubMed  Google Scholar 

  179. Cadepond, F., Ulmann, A. & Balulieu, E.-E. RU486 (MIFEPRISTONE): mechanisms of action and clinical uses. Annu. Rev. Med. 48, 129–156 (1997).

    Article  CAS  PubMed  Google Scholar 

  180. Xia, W. et al. Exploration of the potential mechanism of the Tao Hong Si Wu Decoction for the treatment of postpartum blood stasis based on network pharmacology and in vivo experimental verification. J. Ethnopharmacol. 268, 113641 (2021).

    Article  CAS  PubMed  Google Scholar 

  181. Prankerd, R. J. et al. Pulmonary delivery of an ultra-fine oxytocin dry powder formulation: potential for treatment of postpartum haemorrhage in developing countries. PLoS ONE 8, e82965 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Zhao, W.-D., Wang, L.-P. & Liu, Y.-N. Nursing application values of a new Co(II) complex on postpartum hemorrhage disease. Inorg. Nano-Metal Chem. https://doi.org/10.1080/24701556.2021.1977822 (2021).

  183. Ozalp, G. R., Seyrek-Intas, K., Caliskan, C. & Wehrend, A. Mid-gestation pregnancy termination in rabbits by the progesterone antagonist aglepristone. Theriogenology 69, 1056–1060 (2008).

    Article  CAS  PubMed  Google Scholar 

  184. Haury, J., Seco, A., Goffinet, F. & Lepercq, J. Risk of disseminated intravascular coagulation in postpartum hemorrhage associated with intrauterine infection. J. Gynecol. Obstet. Hum. Reprod. https://doi.org/10.1016/j.jogoh.2023.102626 (2023).

  185. Liu, J. et al. Alkaloids and flavonoid glycosides from the aerial parts of Leonurus japonicus and their opposite effects on uterine smooth muscle. Phytochemistry 145, 128–136 (2018).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

S.E.H. acknowledges support from the American Heart Association (24PRE1200460). A.K.G. acknowledges financial support from the National Institute of Dental and Craniofacial Research (R01 DE032031), the National Institute of Biomedical Imaging and Bioengineering (NIBIB) for the Director’s New Innovator award (DP2 EB026265), National Institute of Neurological Disorders and Stroke (R21 NS121945), Peer Reviewed Medical Research Program (PRMRP) of Department of Defense (DOD) (W81XWH2210932), and President’s Excellence Fund (X-Grants) from Texas A&M University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Author information

Authors and Affiliations

Authors

Contributions

S.E.H. and E.F.L. were instrumental in the conceptualization of the article, conducted the literature review, designed the figures, and were responsible for drafting and revising the manuscript. A.K.G. contributed to the article’s conceptualization, assisted in preparing figures, and contributed in both drafting and editing the manuscript. H.O.C. provided critical review of the manuscript. All authors contributed to the manuscript and approved its final version.

Corresponding author

Correspondence to Akhilesh K. Gaharwar.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Lab Animal thanks Todd Pavek and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hargett, S.E., Leslie, E.F., Chapa, H.O. et al. Animal models of postpartum hemorrhage. Lab Anim 53, 93–106 (2024). https://doi.org/10.1038/s41684-024-01349-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41684-024-01349-8

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing