Misoprostol and cervical ripening
Misoprostol is commonly used to soften and ripen the cervix. Some of the cervical ripening effects of misoprostol are likely due to increased uterine tone. In addition, misoprostol may have a direct effect on the collagen structure of the cervix. To study the effect of misoprostol on the cervix, pregnant patients in the first trimester were randomly assigned to receive misoprostol 200 µg by vaginal self-administration, isosorbide mononitrate (IMN) 40 mg by vaginal self-administration or no treatment the evening prior to pregnancy termination.13 The following day, before uterine evacuation, a cervical biopsy was obtained for electron microscopy studies and immunohistochemistry to assess the presence of enzymes involved in collagen degradation, including matrix metalloproteinase 1 (MMP-1) and matrix metalloproteinase 9 (MMP-9). Electron microscopy demonstrated that pretreatment with misoprostol resulted in a pronounced splitting and disorganization of collagen fibers.13 Compared with misoprostol treatment, IMN produced less splitting and disorganization of collagen fibers, and in the no treatment group, no marked changes in the collagen framework were observed.
Compared with no treatment, misoprostol and IMN pretreatment were associated with marked increases in MMP-1 and MMP-9 as assessed by immunohistochemistry. Misoprostol pretreatment also resulted in a significant increase in interleukin-8 concentration compared with IMN pretreatment and no treatment (8.8 vs 2.7 vs 2.4 pg/mg tissue), respectively.13 Other investigators have also reported that misoprostol increased cervical leukocyte influx and collagen disrupting enzymes MMP-8 and MMP-9.14,15
An open-label clinical trial compared the efficacy of misoprostol versus Foley catheter for labor induction at term in 1,859 patients ≥ 37 weeks’ gestation with a Bishop score <6.16 Patients were randomly allocated to misoprostol (50 µg orally every 4 hours up to 3 times in 24 hours) versus placement of a 16 F or 18 F Foley catheter introduced through the cervix, filled with 30 mL of sodium chloride or water. The investigators reported that oral misoprostol and Foley catheter cervical ripening had similar safety and effectiveness for cervical ripening as a prelude to induction of labor, including no statistically significant differences in 5-minute Apgar score <7, umbilical cord artery pH ≤ 7.05, postpartum hemorrhage, or cesarean birth rate.16
Bottom line
Misoprostol and oxytocin are commonly prescribed in obstetric practice for cervical ripening and induction of labor, respectively. The dose and route of administration of misoprostol influences the effect on the uterus. For cervical ripening, where rapid onset and offset may help to reduce the risk of uterine tachysystole and worrisome fetal heart rate changes, low-dose (50 µg) oral administration of misoprostol may be a preferred dose and route. For the treatment of miscarriage and fetal demise, to stimulate sustained uterine contractions over many hours, buccal and vaginal administration of misoprostol are preferred. Rectal administration is generally inferior to buccal and vaginal administration for stimulating sustained uterine contractions and its uses should be limited. ●
Misoprostol and pyrexia
Common side effects of misoprostol are abdominal cramping, diarrhea, nausea, vomiting, headache, and fever. Elevated temperature following misoprostol administration is a concerning side effect that may require further investigation to rule out an infection, especially if the elevated temperature persists for > 4 hours. The preoptic area of the anterior hypothalamus (POAH) plays a major role in thermoregulation. When an infection causes an increase in endogenous pyrogens, including interleukin-1β, interleukin-6 and tumor necrosis factor, prostaglandins are generated in the region of the POAH, increasing the thermoregulatory set point, triggering cutaneous vasoconstriction and shivering and non-shivering thermogenesis.1 Misoprostol, especially at doses >400 µg commonly causes both patient-reported chills and temperature elevation >38° C.
In a study comparing misoprostol and oxytocin for the management of the third stage of labor, 597 patients were randomly allocated to receive oxytocin 10 units by intramuscular injection or misoprostol 400 µg or 600 µg by the oral route.2 Patient-reported shivering occurred in 13%, 19%, and 28% of patients receiving oxytocin, misoprostol 400 µg and misoprostol 800 µg, respectively. A recorded temperature >38° C occurred within 1 hour of medication administration in approximately 3%, 2%, and 7.5% of patients receiving oxytocin, misoprostol 400 µg, and misoprostol 800 µg, respectively. In another study, 453 patients scheduled for a cesarean birth were randomly allocated to receive 1 of 3 doses of rectal misoprostol 200 μg, 400 μg, or 600 μg before incision. Fever was detected in 2.6%, 9.9%, and 5.1% of the patients receiving misoprostol 200 μg, 400 μg, or 600 μg, respectively.3
References
1. Aronoff DM, Neilson EG. Antipyretics: mechanisms of action and clinical use in fever suppression. Am J Med. 2001;111:304-315. doi: 10.1016/s0002-9343(01)00834-8.
2. Lumbiganon P, Hofmeyr J, Gumezoglu AM, et al. Misoprostol dose-related shivering and pyrexia in the third stage of labor. WHO Collaborative Trial of Misoprostol in the Management of the Third Stage of Labor. Br J Obstet Gynaecol. 1999;106:304-308. doi: 10.1111/j.1471-0528.1999.tb08266.x.
3. Sweed M, El-Said M, Abou-Gamrah AA, et al. Comparison between 200, 400 and 600 microgram rectal misoprostol before cesarean section: a randomized clinical trial. J Obstet Gynaecol Res. 2019;45:585-591. doi: 10.1111 /jog.13883.