By Gharaza Nasir and Sabeeka Malik

Graphic design by Lauren Jones

Every year, thousands of women around the world experience life threatening bleeding following the birth of their children. In 2023, an estimated 260,000 women worldwide died from childbirth, with the leading cause of death being postpartum hemorrhaging (PPH).¹ PPH is defined as more than 500 mL of maternal blood loss in the first 24 hours after childbirth.² One of the main causes of PPH is uterine atony, which refers to the failure of the uterus to contract. Normally during childbirth, following delivery of the placenta, the uterus contracts to compress the blood vessels that are left at the utero-placental interface. If the uterus fails to contract, these blood vessels remain open and bleed freely, potentially leading to severe hemorrhage.²

To combat this, uterotonic medications are administered to stimulate uterine contraction and are critical in the prevention and treatment of PPH. However, large doses of uterotonics, such as oxytocin and carbetocin, can lead to adverse side effects, including nausea, hypotension, and myocardial ischemia.^2,3,4 This raises a key question: what is the optimal dosage of uterotonics that effectively manages PPH while minimizing the risk of adverse effects?

This is what Dr. Mrinalini Balki aims to answer through her research. Dr. Balki moved to Canada to pursue fellowships in Toronto, after completing her medical training in India. She is now a professor in the Departments of Anesthesia, Obstetrics and Gynaecology, and Physiology at the Temerty Faculty of Medicine at the University of Toronto and is a staff anesthesiologist at Mount Sinai Hospital. 

While doing her obstetric anesthesia fellowship, Dr. Balki came across a triennial report from the Confidential Enquiries into Maternal Deaths in the United Kingdom, which documented two deaths following an excessive administration of oxytocin.⁵ Through preliminary clinical research, Dr. Balki and her team determined that only 0.5 units of oxytocin were needed to elicit a uterine response–significantly lower than the then-standard dose of 10 units. Their findings played a monumental role in decreasing the standard dosage of oxytocin to 0.5-1 units for scheduled cesarean deliveries.⁶ This pivotal study further prompted her team to investigate the potential negative effects associated with higher doses of oxytocin. 

One adverse effect of administering excessive dosage of oxytocin during labour is a phenomenon known as desensitization.^2,3 This oxytocin-induced desensitization typically occurs following prolonged use of oxytocin for labour augmentation and can lead to labour arrest,  often necessitating an emergency C-section. Through clinical investigation, Dr. Balki found that patients who had become desensitized to oxytocin bled excessively, posing a barrier to further study this phenomenon in a clinical setting. Her team moved their research to the lab to better study this occurrence and the relationship between uterotonics and uterine contractility. 

At first, Dr. Balki worked with animal models and successfully showed how rodent myometrial tissue (muscular layer of the uterus) responded best to oxytocin in comparison to other utertonics.⁷ Building on these findings, Dr. Balki and her team then moved to study human uterine muscle contractility using an organ bath system.^7,8 This technique involves immersing small pieces of myometrium in a warm oxygen-rich solution that replicates the natural environment of the human body.⁹ Based on insights from these pre-clinical studies, Dr. Balki proposed uterotonic dosing strategies tailored to different patient groups. She also developed the standardized “Rule of Threes” protocol, now widely used worldwide in the clinical management of PPH.¹⁰

The “Rule of Threes” protocol guides clinicians in determining the appropriate amount of uterotonics for the prevention and treatment of PPH, particularly in high stress clinical situations. Physicians rely on two clinical measures to determine the best course of action for patients as outlined in the protocol. The first is determining the uterine contractility, which is assessed by physically examining the uterine tone in response to the drug. The second measure is the extent of uterine bleeding, which is determined by a decrease in hematocrit levels (red blood cell count) or by direct measurement of blood loss. These factors, when considered together, allow Dr. Balki and other clinicians to determine the appropriate dosage of uterotonics to meet each patient’s specific needs. 

Dr. Balki has been a pioneer in translating her research findings into clinical practice, and particularly, in shaping clinical guidelines involving oxytocin dosing.^3,11 “As much research as we do, it holds little value unless it leads to changes in clinical practice,” Dr. Balki highlights. Her work has not only influenced protocols at Mount Sinai Hospital but has also had an international impact.

Obstetrics has advanced significantly from decades ago, when labour pain was considered a natural burden, and women had no access to pain relief during childbirth. Now, it is a prioritized focus of maternal care. Building on this progress, Dr. Balki envisions a future where women’s health is prioritized globally. Despite strides made in recent years, she emphasizes that there is still lots of work to be done, particularly in uncovering the mechanisms behind oxytocin-induced desensitization and addressing other complex challenges in women’s health. In addition to her work on PPH and oxytocin desensitization, she and her team also pioneered the use of procedural spinal ultrasound to more accurately identify the epidural space. This enhances both the safety and success rate of epidural placement for patients with a high body mass index or challenging spinal anatomy requesting labour analgesia.¹² Her team also supports highly specialized fetal surgery programs that allow fetuses to be treated in utero. These procedures can correct or prevent complications early in development, providing the fetus with a better chance at a healthy outcome. Dr. Balki’s work impacts various facets of obstetrics, and she hopes to continue exploring other ways to improve both fetal and maternal health outcomes. 

As the only lab in Canada dedicated to myometrial contractility, Dr. Balki hopes to collaborate with experts nationally and globally to expand the scope of her research. She aims to incorporate more proteomics in her pre-clinical work to begin uncovering the molecular pathways involved in uterine muscle function and desensitization. Beyond reproductive health, her team’s desensitization model may be adapted to study contractility of smooth muscle in other systems, expanding the impact of their work beyond obstetrics. Aside from research, Dr. Balki is deeply committed to knowledge translation and is actively involved in obstetric anesthesia education at Mount Sinai Hospital and the University of Toronto.

Overall, Dr. Balki’s work exemplifies how deeply rooted scientific inquiry can lead to meaningful improvements in maternal care. By bridging the gap between bench research and bedside practice, her lab continues to shape the future of obstetrics. As her team pushes the boundaries of knowledge, the potential for broader impact across women’s reproductive health is only just beginning to unfold. 

References

1. World Health Organization. Maternal mortality. 2025. Available from https://www.who.int/news-room/fact-sheets/detail/maternal-mortality#:~:text=Overview,most%20could%20have%20been%20prevented 
2. Gallos I, Williams H, Price M, et al. Uterotonic drugs to prevent postpartum haemorrhage: a network meta-analysis. Health Technology Assessment. 2019; 23(9).
3. Carvalho JC, Balki M, Kingdom M, et al. Oxytocin Requirements at Elective Cesarean Delivery: A Dose-Finding Study. Obstetrics and Gynecology. 2004; 104(5): 1005-1010. 
4. Moran C, Bhuinneain M, Geary M, et al. Myocardial ischaemia in normal patients undergoing elective Caesarean section: a peripartum assessment. Anaesthesia. 2008; 56(11): 1051-1058. 
5. Crowhurst JA, Plaat F. Why mothers die-report on confidential enquiries into maternal deaths in the United Kingdom 1994-96. Anaesthesia. 1999; 54(3): 207-9. 
6. Osilla EV, Patel P, Sharma S. Oxytocin. In: StatPearls [Internet]. 2025 Jan. Available from https://www.ncbi.nlm.nih.gov/books/NBK507848/
7. Balki M, Cristian AL, Kingdom J. Oxytocin pretreatment of pregnant rat myometrium reduces the efficacy of oxytocin but not of ergonovine maleate or prostaglandin F2 alpha. Reprod Sci. 2010; 17(3): 269-77. 
8. Balki M, Ramachandran N, Lee S, et al. The Recovery Time of Myometrial Responsiveness After Oxytocin-Induced Desensitization in Human Myometrium In Vitro. Anesth Analg. 2016: 122(5): 1508-15
9. Upchurch WJ, Iaizzo PA. In vitro contractile studies within isolated tissue baths: Translational research from Visible Heart Laboratories. Exp Biol Med. 2022: 247(7): 584-597. 
10. Balki M, Tsen L. Oxytocin Protocols for Cesarean Delivery. International Anesthesiology Clinics. Spring. 2014: 52(2): 48-66.
11. Balki M, Ronayne M, Davies S, et al. Minimum oxytocin dose requirement after cesarean delivery for lavor arrest. Obstet Gynecol. 2006: 107(1): 45-50. 
12. Balki M. Locating the epidural space in obstetric patients – ultrasounds a useful tool: continuing professional development. Can J Anaesth. 2010: 57(12): 1111-26.