The American Society of Health-system Pharmacists (ASHP) announced a shortage of oxytocin injection in September 2022. The reason for the shortages has not been disclosed, and some companies have oxytocin on shortages due to manufacturing delays. Fresenius Kabi expects oxytocin to be off of back order in early November 2022. No alternative products are mentioned. [1]
The 2022 International Federation of Gynecology and Obstetrics (FIGO) guidelines recommend the use of carbetocin (not available in the U.S.), ergometrine/methylergometrine, or misoprostol in the cesarean delivery setting where oxytocin is unavailable or its quality can not be guaranteed. The recommendations were based on comparative studies with the majority comparing oxytocin with carbetocin, which is not available in the US. [2]
The Society of Obstetricians and Gynaecologists of Canada (SOGC) issued a statement in 2019 regarding oxytocin management during shortages. They recommend continued and judicious use of oxytocin for eligible patients. Oxytocin waste can be avoided by not drawing up the dose of oxytocin prior to delivery in the event that an alternate route of administration may be required. The hospital pharmacy may be able to mix up intravenous (IV) bags using multidose vials (usually 15 U/250 mL or 30 U/500 mL). Finally, the SOGC recommends considering protocols for alternative approaches, but no alternatives are described. Of note, the American College of Obstetricians and Gynecologists (ACOG) does not have a statement on oxytocin shortage. [3]
A comparison of four international guidelines on postpartum hemorrhage was performed in 2015. While misoprostol was recommended as a second-line preventive medication or when oxytocin is not available for PPH prophylaxis in the New Zealand College of Obstetricians and Gynaecologists guideline, Society of Obstetricians and Gynaecologists of Canada guidelines recommend ergonovine as the second-line agent or when oxytocin is not available. A summary of studies comparing misoprostol versus oxytocin on the prevention of postpartum hemorrhage for vaginal and cesarean deliveries is provided in Table 1. [4]
According to the ACOG guidelines on labor induction, misoprostol can be used intravaginally, sublingually, or orally for cervical ripening or to induce labor. When compared to dinoprostone and oxytocin, intravaginal misoprostol is associated with a lower rate of need for epidural analgesia during labor and an increased rate of vaginal delivery within 24 hours. However, it is associated with more tachysystole with or without changes to the fetal heart rate (FHR). Additionally, misoprostol is associated with longer times to achieve active labor and delivery than oxytocin. It is stated that oxytocin is effective in labor induction and its time to effect is between three to five minutes. Dinoprostone is another suggested option for cervical ripening in term or near-term pregnancies. Dinoprostone can be used intravaginally or intracervically for labor induction. For comparative efficacy, however, it is stated intravaginal misoprostol is either superior or equally efficacious compared to the dinoprostone gel. Compared to placebo or no therapy, dinoprostone can result in an increased chance of delivery within 24 hours, but it does not reduce the incidence of cesarean delivery and is associated with an increased risk of uterine tachysystole with FHR changes. [5]
Similar to FIGO recommendations, the World Health Organization (WHO) also recommends that in settings where oxytocin is unavailable, misoprostol can be used as an alternative for the prevention of PPH. [6]
The World Health Organization (WHO) recommends oral misoprostol (25 mcg every 2 hours) for labor induction, and this recommendation is classified as “strong” recommendation, and the quality of evidence is stated to be moderate. It also provides a strong recommendation for low doses of vaginal prostaglandins for labor induction based on moderate quality evidence. It is stated that low-dose vaginal misoprostol (25 mcg every 6 hours) is also a viable option; however, the strength of recommendation is weak. Of note, it recommends against using misoprostol in those with a history of cesarean section, and it is classified as a strong recommendation. Finally, it states intravenous oxytocin is recommended when prostaglandins are not available, and it recommends against amniotomy alone for labor induction. These are classified as weak recommendations based on moderate quality evidence. In their summary of evidence, it notes that vaginal misoprostol has demonstrated efficacy in achieving vaginal delivery, lower rates of cesarean section delivery, Apgar score being less than 7 at five minutes of life when compared to placebo, expectant management, oxytocin monotherapy, or other prostaglandins. However, it has been associated with a higher rate of uterine hyperstimulation with FHR changes when compared to other prostaglandins, although the risk appears to be lower with lower doses (25 mcg every 6 hours). Oral misoprostol also has demonstrated comparable or favorable outcomes compared to placebo, expected managements, oxytocin, or other prostaglandins in labor induction and relative outcomes. When the two formulations are compared, it states that oral formulation has been associated with a lower risk of Apgar score being less than 7 at five minutes of life compared to vaginal formulations. It notes that misoprostol can also be administered buccally or sublingually; however, there is insufficient evidence to recommend these routes of administration. [7]
For other prostaglandins, WHO states that they are safe and effective compared to placebo, regardless of regimens. When intracervical route is compared to intravaginal route, it states that results are generally favorable for the intravaginal route as a systematic review has suggested a higher risk of not achieving vaginal delivery at 24 hours with intracervical route (risk ratio [RR] 1.26; 95% confidence interval [CI] 1.12-1.4; N= 2,200 participants; N= 11 studies). Additionally, compared to oxytocin monotherapy, evidence shows vaginal prostaglandins results in favorable outcomes. When the gel formulation is compared to tablet or suppository formulations, it notes they all result in similar outcomes; however, gel is associated with a lower risk of hyperstimulation compared to that of a suppository. Regarding doses, when low dose is compared to a higher dose, a lower dose is associated with favorable outcomes in: uterine hyperstimulation with FHR changes, Apgar score being less than 7 at five minutes of life, and cesarean section rates. It suggests the rate of neonatal intensive care unit (NICU) admission may also be lower with a lower dose of prostaglandins compared to a higher dose, although a study shows the results are not significant (RR 0.51; 95% CI 0.24-1.09; N= 955 patients). For oxytocin, although evidence shows favorable outcomes compared to placebo, it is noted that oxytocin did not demonstrate superior efficacy compared to prostaglandins. Finally, regarding amniotomy, evidence shows use of oxytocin with amniotomy is associated with better outcomes in achieving vaginal birth within 24 hours compared to amniotomy alone, supporting the recommendation against use of amniotomy alone for labor induction. [7]
A 2021 network meta-analysis included 46 randomized controlled trials (N= 7,368 patients) to compare oxytocin, carbetocin, misoprostol, ergometrine, carboprost, and combinations of these agents for prevention of PPH during cesarean delivery. Surface under the cumulative ranking curve (SUCRA) scores were calculated to rank each intervention. A SUCRA score is reported as 1 when a treatment is certain to be the best and 0 when a treatment is certain to be the worst. The probability rank order (and SUCRA score) for intraoperative blood loss was carbetocin (0.76), misoprostol (0.65), oxytocin with ergometrine (0.57), oxytocin (0.38), ergometrine (0.36), and oxytocin with misoprostol (0.28). To evaluate the need for additional uterotonics, 37 trials (N= 6,393) were included. Carbetocin was again ranked the best, with a SUCRA score of 0.96, followed by oxytocin with misoprostol (0.73), oxytocin with ergometrine (0.62), oxytocin (0.61), misoprostol (0.47), carboprost (0.31) ergometrine (0.17), and placebo (0.13). The secondary outcome of PPH incidence with > 1,000 mL EBL was evaluated with 13 trials (N= 2,522). The best-ranking intervention was oxytocin with misoprostol, followed by carbetocin, misoprostol, carboprost, oxytocin, and oxytocin with ergometrine. Maternal nausea was evaluated using 16 trials (N= 3,226). The highest ranking intervention was again oxytocin with misoprostol, followed by carbetocin, misoprostol, oxytocin, and oxytocin with ergometrine. Statistical analysis was not performed to evaluate adverse events due to significant heterogeneity between studies. While carbetocin was concluded to be the most effective agent in reducing blood loss and the need for additional uterotonics during cesarean delivery, misoprostol was also highly ranked. [8]
A Cochrane Review states oral misoprostol is an effective labor induction agent for vaginal birth. Compared to placebo, oral misoprostol 50 mcg is associated with a higher rate of vaginal birth within 24 hours (risk ratio [RR] of not achieving vaginal birth 0.16, 95% confidence interval [CI] 0.05-0.49, n= 1 study) and a lower rate of caesarean sections (CS) (RR 0.72, 95% CI 0.54-0.95, I2= 0%). Compared to sublingual route (50 mcg), oral route (50 mcg) shows a higher rate of meconium-stained liquor (RR 10.50, 95% CI 4.07-27.09, n= 1 study); a lower rate of instrumental vaginal birth (RR 0.44, 95% CI 0.22-0.99, n= 1 study); and no difference in CS rate (RR 1.56; 95% CI 0.74-3.26, n= 1 study). Finally, compared to vaginal route, there is no difference in vaginal delivery (RR of not achieving vaginal delivery 1.08, 95% CI 0.86-1.36, I2=84%), uterine hyperstimulation with FHR changes (RR 0.71, 95% CI 0.47-1.19; I2=53%), and CS rate (RR 0.93, 95% CI 0.81-1.07, I2= 44%). Moreover, no differences are seen in serious neonatal morbidity or perinatal death, serious maternal morbidity or death, serious maternal complications, uterine rupture, oxytocin augmentation, uterine hyperstimulation without FHR changes, need for epidural analgesia, instrumental vaginal delivery, neonatal intensive care unit admission rate, neonatal encephalopathy, perinatal death, overall maternal side effects, and patient satisfaction rates. However, oral route is associated with a lower rate of Apgar score less than seven at five minutes (RR 0.60, 95% CI 0.44-0.82, I2= 0%). In subgroup analyses of doses, only 50 mcg shows a significant outcome in lower Apgar scores. Data also show that oral route is associated with a lower rate of postpartum hemorrhage (RR 0.57, 95% CI 0.34-0.95, I2= 0%). However, oral route is associated with higher meconium-stained liquor (RR 1.22, 95% CI 1.03-1.44, I2= 17%). The authors further discuss that data show large heterogeneity, which limits the comparison between vaginal and oral routes; however, given the improved outcomes seen with Apgar scores and postpartum hemorrhage, as well as possibility of greater patient acceptance, the authors suggest oral route may be preferred over vaginal route. Regarding dosage, the review included various doses (25-200 mcg). It is suggested optimal dose of oral misoprostol is 20-25 mcg every two hours because lower doses are associated with lower rates of hyperstimulation, and this dose has shown lower rates of CS when compared to vaginal dinoprostone. [9]