Minimize Risk When Using Misoprostol Off Label

OB/GYN News, August 1, 2001 by Winnie Anne Imperio

AMELIA ISLAND, FLA. -- The off-label use of misoprostol for the induction of labor is supported by good clinical evidence and the American College of Obstetricians and Gynecologists, Dr. B. Denise Raynor said at an ob.gyn. update sponsored by Emory University.

Following ACOG recommendations on obstetric use of misoprostol puts ob.gyns. in the best medicolegal position when using this agent, said Dr. Raynor of Emory University in Atlanta.

Misoprostol is licensed in the United States only for the prevention of gastric ulcers associated with the use of nonsteroidal anti-inflammatory drugs; it carries a warning against its use during pregnancy Still, the drug has been widely used off label for cervical ripening and labor induction.

In August of last year, Searle, the manufacturer of misoprosrol (Cytotec), sent a letter to health care providers reminding them that the drug is contraindicated in pregnancy and could result in serious adverse events, including maternal and fetal death.

A few months later, ACOG wrote a letter to the Food and Drug Administration in which it reaffirmed a previous committee opinion that misoprostol is safe and effective when used appropriately in pregnant women.

In that letter, ACOG recommended the following practices to minimize risk in patients who are undergoing cervical ripening or labor induction in the third trimester:

* Consider using 25 [micro]g for the initial dose.

* Do not administer doses to patients more frequently than every 3-6 hours.

* Do not administer oxytocin to patients less than 4 hours after the last misoprostol dose.

* Do not use misoprostol in patients with a previous cesarean delivery or prior major uterine surgery.

Dr. Raynor added that physicians should have a pharmacist cut the small, unscored misoprostol tablet. The tablet should be placed in the posterior fornix, and excessive lubrication should be avoided, she said.

She advised that all hospitals have a protocol for the use of misoprostol for labor induction. (See box.)

There is good evidence to suggest that misoprostol is safe and effective when used judiciously in pregnancy Dr. Raynor said.

For example, in a metaanalysis of eight randomized, controlled trials involving more than 900 patients, those who received misoprostol required less oxytocin, were less likely to have a cesarean section, and were more likely to have a successful induction, compared with patients who received either prostaglandin [E.sub.2] gel or a vaginal insert, oxytocin, or placebo (Obstet. Gynecol. 89[4]:633-42, 1997). Misoprostol doses varied from 25 [micro]g every 2 hours to a single dose of 100 [micro]g.

Compared with the other patients, those who received misoprostol had an odds ratio of 0.67 for having a cesarean section and 2.64 for having a spontaneous vaginal delivery. The odds ratio for oxytocin augmentation was 0.3.

Tachysystole was a big problem with an odds ratio of 2.7, but it did not appear to affect neonatal outcome, Dr. Raynor said. There was no difference between patients who received misoprostol and control patients in admissions to the neonatal intensive care unit and 5-minute Apgar scores.

Vaginal administration of misoprostol is the preferable route, though there has been a lot of interest in oral misoprostol because it can be administered by nurses and is associated with less patient discomfort, Dr. Raynor said. However, there are fewer studies involving obstetric use of the oral formulation, and the appropriate dose still has not been determined.

The oral formulation also appears to be less effective. Serum levels of oral misoprostol peak within 30 minutes and then decline rapidly. When the vaginal route is used, serum levels peak in 1-2 hours but are maintained for a longer period of time.

There are very little data on the induction of labor with misoprostol in women with premature rupture of membranes.

One study showed that misoprostol and oxytocin were equally effective and resulted in no difference in maternal or neonatal morbidity (Am. J. Obstet. Gynecol. 179[1]:94-99, 1998).

Dr. Raynor added that she has heard of people using misoprostol for labor augmentation.

She cautioned, however, that this technique is probably not a good idea because there are no published data on this practice.

Sample Protocol For Misoprostol Use in Labor

Dosing

25 [micro]g every 4 hours, up to 6 doses

Reasons to Discontinue Use

Two or more contractions in a 10-minute period

Bishop score [greater than]8

Cervix that is 3 cm dilated or more than 80% effaced

Active labor

Nonreassuring fetal heart rate tracings

Rupture of membranes

Patient Inclusion Criteria

Singleton gestation

Bishop score [less than]6

Cephalic presentation

Patient Exclusion Criteria

Multiple gestation

Heavy vaginal bleeding

Fetal weight [less than]1,800 g

Contractions per hour [greater than]6

Nonreassuring fetal heart rate tracings

Parity [greater than]6

Hypersensitivity to prostaglandin products

Renal or hepatic dysfunction

Previous uterine surgery

Any contraindication to vaginal delivery

Source: Dr. B. Denise Raynor