4/15/23njm

ORAL TITRATED MISOPROSTOL FOR INDUCTION OF LABOR: ANMC

BACKGROUND

The incidence of labor induction has been steadily rising, and the rate of induced labor currently ap-
proaches 25 per cent, owing to the large number of referred patients with a medical indication for delivery,
principally postdates pregnancy, hypertensive disease of pregnancy, and other maternal and fetal condi-
tions necessitating delivery. Induction of labor can be a long and tedious process and involves considera-
ble resource expenditure. The incidence of cesarean delivery is increased following induced labor, partly
due to the risk condition for which the procedure was undertaken, and partly due to a lack of cervical
“ripeness” or readiness for labor. The Bishop score is a reasonable clinical guide that references the cer-
vical shortening, softening, and dilation that takes place as pregnancy advances. Bishop scores of 5 or
less are considered unfavorable, and are inversely related to the success of the induction and the length
of labor.

Both mechanical (Foley balloon, Atad balloon, Cook catheter system, seaweed based dilators) and phar-
macologic methods (oxytocin and various prostaglandins, including misoprostol (Cytotec), dinoprostone
(Cervidil) have been used to ripen the unfavorable cervix. Review of the current evidence suggests that
the prostaglandin misoprostol, administered either orally or intravaginally, are generally considered the
more effective agent for cervical ripening and induction of labor. This drug has a good safety profile at the
lower dosage range, and is convenient to use, but there are limitations to its use, particularly in women
with a uterus previously scarred as a result of cesarean delivery.
Misoprostol is associated with uterine tachysystole, which may result in fetal heart rate abnormalities, an
effect which is both dose and route of administration dependent. This adverse effect may result in the in-
duction being terminated urgently by a cesarean delivery, which otherwise would not have been indicat-
ed. The optimum dose of misoprostol at present is considered to be 25 mcg or less, administered by the
oral or vaginal route, Dosing of the drug is problematic in our setting as misoprostol is only supplied as
100 or 200 mcg tablets, making accurate fractionation of the drug into less than 50 mcg fragments virtual-
ly impossible. Likewise, the drug may not be every distributed within the inert material of the tablet, mak-
ing failure of response, or an exaggerated response, unpredictable.

In response to this challenge, dissolving the 200 mcg tablet in 200 mL of water is proposed as an accu-
rate, safe, and efficacious method of using the drug in safe low dose 20 mL/20 mcg aliquots, and is re-
ferred to as use of low dose titrated oral misoprostol. The dosing interval of every 2 hours for oral miso-
prostol is based on the known pharmacokinetics of the drug, which, in contradistinction to vaginal dosing,
when the drug is administered by the oral route, requires 30 to 60 minutes to achieve peak plasma levels,
but is then promptly metabolized, and is essentially undetectable after 120 minutes.
(see diagram - after Zeiman et al).

Candidates for ripening/induction with low dose titrated oral misoprostol

a. Women at term with an unfavorable cervix (defined as a Bishop score 5 or less) with a medical indi-
cation for delivery are reasonable candidates for use of this protocol.

b. Medical indications for delivery where women would be considered candidates for induction of
labor, examples include but not limited:
-Postdates pregnancy (41 weeks or more of gestation)
-Hypertensive disease of pregnancy
-Other indications, (fetal growth restriction, diabetes mellitus, other maternal or fetal conditions)

c. Women who would NOT be candidates for this protocol include those with:
-Prior cesarean delivery (or other prior uterine incision)
-Non-reassuring antenatal fetal surveillance (significant persistent decelerations of the fetal heart
rate noted on cardiotocography requiring urgent delivery)
-Active labor already in process (more than 3 palpable contractions lasting greater than 30 sec-
onds in 10 minutes, or cervical dilation greater than 4 cm)
-Any known obstetric contraindication to labor (e.g., placenta previa, malpresentation, active her-
pes simplex infection, etc.)

PROCEDURE

a. Prior to beginning the drug, the patient will have a 20-minute pre-ripening cardiotocogram.
b. If any of these are met, the patient would not be considered a ripening candidate:
-baseline fetal heart pattern abnormalities
-Bishop score of 6 or greater
-regular painful uterine contractions every 3 minutes lasting 30 seconds
-in active labor.

c. Women will be dosed as follows:

1. Misoprostol 200 mcg will be dissolved in 200 mL of tap water, constituting a solution of 20 mcg in
20 mL. This solution may be used for up to 48 hours. (USP 795)
2. An initial dose of 20 mcg (20 mL measured in a syringe) will be given by mouth, and the time of
the first dose recorded.
-the same dose will be repeated every hour for 3 hours (total of 4 doses).
3. Patients may ambulate and take oral fluids and light foods ad lib during the ripening/induction
procedure.
 4. The patient will be monitored with the fetal heart tracing and cardiotocogram (CTG) for 20
minutes after receiving the medication. If fetal tolerance has been assured, then the patient can
be off the monitor for 20 minutes. The patient is then placed back on the fetal heart tracing and
cardiotocogram (CTG) 20 minutes prior to the next dose.
5. Uterine tachysystole, (defined as more than 5 contractions in 10 minutes, averaged over a 30 mi-
nute window) without worrisome fetal heart rate changes, will not be an indication to stop the rip-
ening-induction procedure. If the fetal heart tracing is reassuring, then the medication can be ad-
vanced per guideline.
6. Tachysystole with fetal heart rate abnormalities (Category II or III tracings should result in miso-
prostol not being given in the subsequent hour, or until the abnormal pattern has resolved. Lat-
eralization, oxygen, and a fluid bolus will be given as per routine.
7. If the FHR remains reassuring, and regular uterine contractions (3 contractions every 10 minutes
lasting at least 30 seconds) have not ensued after 4 hours:
-the dose may be increased to 40 mcg (40 mL) every 2 hours until active labor is
established.
8. The patient will be monitored with the fetal heart tracing and cardiotocogram (CTG) for 20
minutes after receiving the medication. If fetal tolerance has been assured, then the patient can
be off the monitor for 20 minutes. The patient is then placed back on the fetal heart tracing and
cardiotocogram (CTG) 20 minutes prior to the next dose.
9. A cervical exam will be performed 12 hours after the first dose of misoprostol has been given. If
active labor (defined as above) has still not begun in 12 hours, misoprostol 60 mcg will be contin-
ued at 2 hourly intervals as long as the fetal heart rate pattern is reassuring.
10. The patient will be monitored with the fetal heart tracing and cardiotocogram (CTG) for 20
minutes after receiving the medication. If fetal tolerance has been assured, then the patient can
be off the monitor for 20 minutes. The pt is then placed back on the fetal heart tracing and cardi-
otocogram (CTG) 20 minutes prior to the next dose.
11. A cervical exam will be performed 24 hours after the first dose of misoprostol has been given. If
active labor has still not begun in 24 hours, the provider will decide on the patient’s management
12. If active labor is established, but then contractions become inadequate (less than 3 contractions
in 10 minutes lasting 30 seconds over a 2 hour period), or labor is arrested (no further dilation
over 2 hours), then the labor may be augmented with titrated oral misoprostol
-beginning at 5 mcg every hour, progressing to 10 mcg every hour, or 20 mcg every hour
(maximum dose permitted) every hour until adequate labor progress is established.
-The patient will be monitored with the fetal heart tracing and cardiotocogram (CTG) for
20 minutes after receiving the medication. If fetal tolerance has been assured, then the
patient can be off the monitor for 20 minutes. The pt is then placed back on the fetal heart
tracing and cardiotocogram (CTG) 20 minutes prior to the next dose.

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Reviews
Cheng SY. Individualized misoprostol dosing for labor induction or augmentation: A review. World J Ob-
stet Gynecol 2013; 2(4): 80-86 http://www.wjgnet.com/2218-6220/full/v2/i4/80.htm#B23 (Accessed 4/15/23)

Vogel JP, West HM, Dowswell T. Titrated oral misoprostol for augmenting labour to improve maternal and
neonatal outcomes. Cochrane Database Syst Rev. 2013 Sep 23;(9):CD010648. doi:
10.1002/14651858.CD010648.pub2. (Accessed 4/15/23)

Cheng SY. How to Manage Labor Induction or Augmentation to Decrease the Cesarean
Deliveries Rate, Cesarean Delivery, Dr. Raed Salim (Ed.), 2012.
ISBN: 978-953-51-0638-8, (Accessed 4/15/23)
Available from: www.intechopen.com
https://www.intechopen.com/books/cesarean-delivery/how-to-manage-labor-induction-or-augmentation-with-titrated-oral-misoprostol-to-
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(Accessed 4/15/23)

Revised 4/15/23 njm

Revised 4/16/21 njm
Revised 5/31/17 njm
Written 3/28/17njm
 Table 1: Cervical Ripening – Oral Titrated Misoprostol

20 mcg in 20 mL Q one hr 4 doses Monitor 20 min

pre-dose

Monitor 20 min

post-dose

40 mcg in 40 mL Q two hrs 4 doses Monitor 20 min

pre-dose

Monitor 20 min

post-dose

60 mcg in 60 mL Q two hrs 6 doses Monitor 20 min

pre-dose

Monitor 20 min

post-dose
 Table 2: Augmentation – Oral Titrated Misoprostol

5 mcg in 5 mL Q one hr One dose Monitor 20 min

pre-dose

Monitor 20 min

post-dose

10 mcg in 10 mL Q one hr One dose Monitor 20 min

pre-dose

Monitor 20 min

post-dose

20 mcg in 20 mL Q one hr Until active labor Monitor 20 min

pre-dose

Monitor 20 min

post-dose