Key points
-
Misoprostol is a prostaglandin E1 (PGE1) analogue that has been on the World Health
Organization (WHO) List of Essential Medicines since 2005.
-
Brazil has one of the most restrictive regulations in the world related to the use
of misoprostol establishing it is exclusively for hospital use with special control,
and sale, purchase and advertising prohibited by law.
-
Misoprostol is currently the reference drug for pharmacological treatment in cases
of induced abortion, both in the first trimester of pregnancy and at more advanced
gestational ages.
-
Misoprostol is an effective medication for cervical ripening and labor induction.
-
Misoprostol is an essential drug for the management of postpartum hemorrhage.
Recommendations
-
The use of misoprostol is recommended for the following situations: legal abortion,
uterine evacuation due to embryonic or fetal death, cervical ripening before labor
induction (uterine cervix maturation), labor induction and management of postpartum
hemorrhage.
-
Misoprostol 800 mcg vaginally (four 200 mcg pills) is recommended for uterine evacuation
in pregnancy loss up to 13 weeks.
-
In cervical preparation for surgical abortion at less than 13 weeks of pregnancy,
the use of misoprostol 400 mcg vaginally 3-4 hours before the procedure is recommended.
-
The use of misoprostol alone according to the gestational age for uterine evacuation
is recommended for termination of pregnancy in legal abortion.
-
The use of vaginal misoprostol according to the gestational age is recommended for
uterine evacuation in case of fetal death: at 13-26 weeks, 200 mcg every 4-6 hours;
at 27-28 weeks, 100 mcg every 4-6 hours; and over 28 weeks, 25 mcg every six hours.
-
The use of misoprostol at an initial dose of 25 mcg vaginally every 4-6 hours is recommended
for cervical ripening and induction of labor with a live fetus in pregnancies over
26 weeks.
-
The use of misoprostol for cervical ripening and induction of labor with a live fetus
is not recommended in women with a previous cesarean section due to the greater risk
of uterine rupture.
-
Misoprostol is a safe and effective option for women with premature rupture of membranes
and unfavorable uterine cervix, as long as they do not have contraindications for
taking the medication, for example, previous cesarean section.
-
Rectal misoprostol 800 mcg is recommended as part of the drug treatment of postpartum
hemorrhage.
-
In Brazil, misoprostol should be made available to all health services at all levels
of care, and it is desirable that outpatient use be allowed, when indicated.
Background
Misoprostol is a synthetic analogue of prostaglandin E1 (PGE1) with gastric secretion
inhibitory and mucosal protection properties through the production of bicarbonate
and mucus. It was first approved to be used to protect the stomach mucosa in patients
using non-steroidal anti-inflammatory drugs.[1] This drug has been widely used in obstetric practice to induce abortion and as an
agent to promote cervical ripening in induction of labor at term. The combination
of misoprostol and mifepristone is used in medical abortions with a good safety profile
in several countries. In Brazil, the commercialization of misoprostol is controlled
for use in the hospital environment, in labor induction and legal abortion, or in
cases of emptying of the uterus in abortion or retained dead fetus. There is widespread
debate about the standardization of dosage in the use of misoprostol. Higher doses
of misoprostol are used for induced and retained abortions, and much lower doses are
used for cervical ripening and labor induction in term pregnancies.[2] It is also indicated for the treatment of postpartum hemorrhage (PPH).
What are the pharmacokinetic properties of misoprostol?
What are the pharmacokinetic properties of misoprostol?
Misoprostol is a synthetic analogue of PGE1. It is metabolized in the liver, deesterified
and becomes the active metabolite, misoprostol acid. It has the ability to bind to
uterine smooth muscle cells, increasing the strength and frequency of uterine contractions.[3] In the uterine cervix, it also promotes the breakdown of collagen in the connective
tissue and a reduction in cervical tonus.[4] Misoprostol can be used orally, vaginally, sublingually and rectally. In oral administration,
the drug reaches its maximum peak 20-30 minutes after ingestion, remaining detectable
for up to four hours. Misoprostol administered sublingually is absorbed more quickly
and has higher peak concentrations than when administered orally, which tends to cause
higher rates of gastrointestinal side effects at any dose.[5] Overall bioavailability of the drug used vaginally is greater, since the absorption
is slower than in other routes, and the maximum plasmatic peak is reached in 40-60
minutes, remaining stable up to two hours after application. The vaginal route also
allows for greater effects on the cervix and uterus.[6] The pharmacokinetics of rectal misoprostol is similar to that of vaginal misoprostol,
although with a lower overall bioavailability and a significantly lower peak plasma
level.[7] It has been demonstrated that levels of misoprostol in breast milk are known to
peak and decline rapidly with an average half-life of around one hour. Although it
normally appears in colostrum and milk, the low levels detected suggest that a minimal
amount of misoprostol could potentially be ingested by the newborn.[4]
What are the adverse effects and contraindications for using misoprostol?
What are the adverse effects and contraindications for using misoprostol?
Although other prostaglandins can cause myocardial infarction and bronchospasm, misoprostol
is not associated with these effects. Toxic doses have not been well established and
cumulative doses of up to 2,200 mcg in 12 hours are well tolerated without significant
adverse effects.[8] A case of non-lethal misoprostol overdose was reported after ingestion of 6,000
mcg, coursing with hyperthermia, rhabdomyolysis, hypoxemia and metabolic acidosis.[9] One fatal case was reported after ingestion of 12,000 mcg (60 tablets), causing
gastrointestinal bleeding with gastric and esophageal necrosis and organ failure.[10] The most common adverse effects of misoprostol are nausea, vomiting, diarrhea, abdominal
pain, chills, shivering and fever. All these effects are dose-dependent.[8] Gastrointestinal effects may occur in approximately 35% of women and are more common
after oral or sublingual administration. Diarrhea is the most common adverse effect
and is usually mild and self-limited to one day.[11] Shivering and fever are also transitory effects and may occur in 28% and 7.5%, respectively,
of women who used 600 mcg of misoprostol orally.[12] The occurrence of fever and shivering from misoprostol in the active management
of the third stage favors the routine use of oxytocin as the drug of choice for the
prevention of hemorrhage.[13] Although dose-dependent, uterine hyperstimulation is one of the most frequent adverse
effects in labor induction. The risk of uterine hyperstimulation was high with high
doses of misoprostol used in the past. With low doses (≤50 mcg of initial dose), the
risk is similar to that of dinoprostone, 4-12%, depending on the route and dosage.[11] In a Cochrane meta-analysis, the risk of hyperstimulation with alteration of fetal
heart rate was significantly lower with low-dose oral misoprostol (3.4%) compared
to vaginal dinoprostone (7.0%; RR: 0.49; 0.40-0.59). In that same meta-analysis, a
lower risk of hyperstimulation with fetal cardiac alteration was also found with oral
misoprostol (3.9%), compared to the vaginal route (5.7%; RR: 0.69; 0.53-0.92).[14] Fetal distress, the presence of meconium in the amniotic fluid and uterine rupture
may occur as a result of hyperstimulation (hypersystole or tachysystole with or without
hypertonia).[15] Uterine rupture is the most feared adverse effect of labor induction, especially
in women with previous uterine scar. Although extremely rare, there are case reports
of uterine rupture during first-trimester abortion induction. Most cases of uterine
rupture have been described in third-trimester inductions and associated with previous
uterine scar or other risk factors.[7] The risk of uterine rupture in women with induction of labor for vaginal delivery
after cesarean section with misoprostol is 6-12%.[11] Therefore, this is usually a contraindication for using the drug.[16]
[17] It is important to emphasize that misoprostol can be used in the second trimester
in women with a previous cesarean section, since most studies point to a low risk
of uterine rupture.[17] A meta-analysis identified that this risk is not significantly different when the
woman has had a previous cesarean section (0.47%) compared to no uterine scar (0.08%;
RR: 2.36; 0.39-14.32), although it is significantly higher with two or more previous
cesarean sections (2.5%; RR: 17 ,55; 3-102.8).[18]
What are the teratogenic effects of misoprostol?
What are the teratogenic effects of misoprostol?
The Food and Drug Administration (FDA) classifies misoprostol as a category X drug
(evidence of teratogenesis in animals and humans) in the first and second trimesters
of pregnancy. Animal studies have shown a significant reduction in fertility with
the use of high doses (6.25 to 625 times the maximum human therapeutic dose). In pregnant
rabbits, doses of 300 to 1,500 mcg/kg of misoprostol on days 7-19 of embryogenesis
have been associated with teratogenic effects.[19] Misoprostol-related malformations were initially described in case reports in humans.[20]
[21]
[22] These findings were subsequently confirmed in case-control and prospective studies
and meta-analyses.[23]
[24]
[25]
[26] Most of these data come from Brazil and involve cases of malformations related to
failed abortion with the use of misoprostol. In countries where abortion is legally
permitted, patients rarely continue with the pregnancy after a failed abortion with
misoprostol. In humans, there are several malformations associated with the use of
misoprostol in the first trimester of pregnancy, such as: Moebius sequence (compromise
of the VI and VII cranial nerves with paralysis of the eyes and facial muscles), arthrogryposis,
transverse reduction of extremities and limbs, congenital clubfoot, hydrocephalus,
encephalocele, meningocele, hemifacial microsomia, severe trismus.[21]
[26]
[27] The risk of any malformation associated with the use of misoprostol is 2.64 (95%
confidence interval [CI]: 1.03-6.75) compared to the unexposed group,[25] while the risks for the Moebius sequence and transverse limb reduction were 25.31
(95% CI: 11.11-57.66) and 11.86 (95% CI: 4.86-28.90), respectively.[24] The teratogenic mechanism attributed to fetal malformations and alterations is a
result of vascular disruption caused by intense uterine contractions and vaginal bleeding
leading to embryonic hypoperfusion with tissue hypoxia, endothelial cell damage and
tissue loss.[24]
[28]
[29] Fetal malformations and impairments depend on the developmental stage of the embryo,
and the greatest risks are related to the use in the first trimester of pregnancy.
It is still controversial if the risk of teratogenicity is dose-dependent, since studies
indicate, for example, the association of severe malformations such as hydrocephalus
with both low (200 mcg) and high doses (800 mcg) of misoprostol.[26]
[30] Hence, it is not possible to provide certainty regarding the absence or severity
of alterations after using any dose of misoprostol in the first trimester of pregnancy.
How to use misoprostol in uterine evacuation after embryonic death?
How to use misoprostol in uterine evacuation after embryonic death?
Misoprostol is used for uterine evacuation in first trimester pregnancy loss. On ultrasound
examination, pregnancy loss can be characterized by the following aspects: presence
of gestational sac without yolk sac or embryo and with mean diameter ≥ 25 mm; embryo
with crown-rump length greater than or equal to 7 mm without cardiac activity; no
embryo with a heartbeat two weeks after an examination demonstrating an empty gestational
sac or no embryo with a heartbeat at 11 or more days after an examination demonstrating
a gestational sac with yolk sac. In these situations, three approaches are possible:
expectant management, mechanical uterine evacuation, or pharmacological evacuation.[31] The most effective and safe way to promote pharmacological uterine evacuation is
the combination of mifepristone 200 mg followed by misoprostol (1-2 days later), with
an efficacy rate of around 90% versus 70% when using misoprostol alone.[32]
[33] Given the unavailability of mifepristone, since its use is not regulated in Brazil,
the isolated use of misoprostol is a reasonable alternative. There are several protocols,
and the International Federation of Gynecology and Obstetrics (FIGO)[17] and the World Health Organization (WHO)[34] recommend the administration of 800 mcg vaginally, sublingually or buccally (four
200 mcg tablets). FIGO recommends a second dose three hours later.[17]
[34] There are no clear definitions regarding the interval and number of complementary
doses, if necessary. Longer dosing intervals have the benefit of exposing the patient
to a reduced risk of adverse effects. On the other hand, shorter dosing intervals
(closer to three hours) may be necessary to generate sufficient uterine activity,
particularly if misoprostol is given buccally or sublingually. Although uterine hyperstimulation
is rare, particularly in the first trimester, the risk may increase with shorter dosing
intervals. In pregnancies of less than 12 weeks, 1-3 doses of misoprostol are usually
sufficient to expel the uterine contents.[35] The main advantages of using misoprostol include avoiding uterine perforation and
formation of synechiae, reduced risks of sequelae inherent to the mechanical dilation
of the cervix, and no need for anesthetic procedure. Disadvantages include a longer
resolution time (sometimes days), higher prevalence of some symptoms such as cramps,
bleeding, nausea, fever and chills, occasional need for surgical complementation and
blood transfusion, and the woman's anxiety because of the waiting.[31]
[36] When opting for mechanical evacuation of the uterus, misoprostol can be used to
prepare the cervix, avoiding or facilitating instrumental dilation before aspiration
or curettage. The recommended dose is 400 mcg vaginally 3-4 hours before the procedure.
If available, the sublingual route can be used in a shorter time interval (one hour).[17]
[31] Misoprostol 800 mcg vaginally (four 200 mcg tablets) is recommended for uterine
evacuation in pregnancy loss up to 13 weeks.
The use of misoprostol in legal abortion
The use of misoprostol in legal abortion
Brazil has one of the most restrictive regulations related to induced abortion - induced
abortion is only legally permitted in cases of pregnancy resulting from rape, risk
to the woman's life and fetal anencephaly – and to the use of misoprostol in the world.
In a study of countries in Africa, Asia and Latin America, Brazil was close only to
Vietnam among those with greater restrictions on access to medical abortion in the
world.[37] Brazil is the only South American country where misoprostol is not available directly
to women, whether in health services or for sale in pharmacies.[38] Contrary to what one might imagine, these barriers fail to reduce the use of misoprostol
by women, since half of illegal abortions in the country are performed with this drug.[39] The regimen of use of misoprostol alone recommended for the induction of abortion
in cases provided for by law, is shown in [chart 1].[1]
[17]
[34] The drug is used until expulsion of products of conception. In the first trimester,
three doses of misoprostol are usually sufficient to complete the treatment.[40]
Chart 1.
Regimen of use of misoprostol alone according to gestational age for uterine evacuation
in induced abortion/legal abortion
|
Gestational age
|
Dosage
|
|
Up to 14 weeks
|
misoprostol 800 mcg (vaginally, sublingually, or buccally) every 3 hours
|
|
14- 24 weeks
|
misoprostol 400 mcg (vaginally, sublingually, or buccally) every 3 hours
|
|
25-28 weeks
|
misoprostol 200 mcg (vaginally, sublingually, or buccally) every 4 hours
|
|
Over 28 weeks
|
misoprostol 100 mcg every 6 hours
|
Source: Krugh M, Maani CV. Misoprostol. In: StatPearls [Internet]. Treasure Island: StatPearls
Publishing; 2022 [cited 2022 Dec 15]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539873/. Morris JL, Winikoff B, Dabash R, Weeks A, Faúndes A, Gemzell-Danielsson K, et al.
FIGO's updated recommendations for misoprostol used alone in gynecology and obstetrics.
Int J Gynaecol Obstet. 2017;138(3):363-6. doi: 10.1002/ijgo.12181. World Health Organization.
Abortion care guideline [Internet]. Geneva: WHO; 2022 [cited 2022 Oct 31]. Available
from: https://www.ncbi.nlm.nih.gov/books/NBK578942/pdf/Bookshelf_NBK578942.pdf. [1]
[17]
[34]
In cervical preparation prior to surgical abortion in pregnancies over 12-14 weeks,
the use of misoprostol 400 mcg (vaginally or orally) 2-3 hours before surgical treatment
is routinely recommended.[34] If sublingual route is used, the time until the surgical procedure can be reduced
to 1-2 hours.[40] Although cervical preparation should not be used routinely in pregnancies before
12 weeks, it can be beneficial in specific cases such as women at increased risk of
complications during cervical dilation, for example, those with cervical anomalies
or a history of cervical surgery.[34]
[41] Safety and efficacy data of the misoprostol treatment regimen alone for induced
abortion were published in a randomized clinical trial of 2,066 women who received
three doses of misoprostol 800 mcg.[42] In that study, only 0.04% of women had vaginal bleeding requiring return to the
hospital. There were no serious adverse events among study participants. The WHO cites
the possibility of the combined use of letrozole and misoprostol as safe and effective
in terminating pregnancies of less than 13 weeks in scenarios where mifepristone is
not available (letrozole 10 mg orally each day for three days followed by misoprostol
800 mcg sublingually on the fourth day).[34]
Is it safe to use misoprostol on an outpatient basis?
Is it safe to use misoprostol on an outpatient basis?
The use of misoprostol on an outpatient basis is considered effective and safe for
the treatment of induced abortion, especially in the first 12 weeks of pregnancy.
The use of misoprostol during this period has minimal adverse effects, such as diarrhea,
vomiting, nausea and fever, which can be easily treated by professionals outside the
hospital setting.[42]
[43]
[44] Outpatient use can reduce costs for both the health system and the hospital due
to the waiver of hospitalization, as well as for women, since they do not need to
remain in hospitals and in most cases, can receive adequate care at health units close
to their homes.[34] In cases of induction of labor, the use of misoprostol in a hospital environment
is recommended.
How to induce emptying of the uterus with misoprostol in fetal death at 13-24 weeks?
How to induce emptying of the uterus with misoprostol in fetal death at 13-24 weeks?
When the diagnosis of fetal death is established, the health professional assisting
this pregnant woman and her family must always be able to answer the posed questions
with empathy and embracement, even if there are no answers to all. A systematic review
including 14 controlled and randomized studies that evaluated the use of misoprostol
in fetal death in the second and third trimesters found 100% effectiveness in uterine
evacuation within 48 hours.[45] Randomized studies support the use of misoprostol as a first-line agent in the induction
of labor in fetal death at 20-24 weeks, including in patients with a history of previous
cesarean section.[46]
[47] Several intervals between doses, dosages and routes of administration are described,
but none showed clear evidence of superiority. The regimen of misoprostol recommended
for uterine evacuation in the case of fetal death at 14-24 weeks of gestational age
is 400 mcg vaginally every 4-6 hours.[34]
How to use misoprostol in the induction of stillbirth after 24 weeks?
How to use misoprostol in the induction of stillbirth after 24 weeks?
In cases of fetal death after more than 24 weeks, labor induction depends on the conditions
of cervical maturation. In patients with a favorable cervix (Bishop index ≥ 6), labor
induction can be started with oxytocin without the use of misoprostol for previous
cervical ripening. In patients with an unfavorable cervix and without previous uterine
scar, misoprostol is the agent of choice for preparing the cervix and inducing labor.[17]
[34]
[48] The following regimens are recommended:
-
25-26 weeks: misoprostol 400 mcg vaginally or sublingually every 4-6 hours;
-
27-28 weeks: misoprostol 100 mcg vaginally or sublingually every 4-6 hours;
-
Over 28 weeks: misoprostol 25 mcg vaginally every six hours.
In patients with previous segmental scarring and unfavorable cervix at 24-28 weeks,
cervical preparation can be performed with a mechanical method (transcervical balloon)
followed by the use of oxytocin. The use of misoprostol seems to be an acceptable
alternative at this gestational age, since the risk of uterine rupture is low. In
a review study in which misoprostol was used at this gestational age, the risk of
uterine rupture was 0.28% (95% CI: 0.08-1.00) in patients with a previous cesarean
section versus 0.04% (95% CI: 0.01-0.20) in patients without a previous cesarean section.[18]
[49]
[50] However, at 24-26 weeks, low doses of misoprostol (100 mcg to 200 mcg per dose)
may be suggested.[50] In pregnancies over 28 weeks, cervical preparation for labor induction should be
performed in accordance with recommendations for parturient women with a live fetus.
How to perform maturation of the uterine cervix and induction of labor with misoprostol?
How to perform maturation of the uterine cervix and induction of labor with misoprostol?
In the labor induction process, when the situation of the uterine cervix is unfavorable,
a maturation process is recommended to shorten the duration of induction and increase
the chance of vaginal delivery. When the Bishop score is less than 6, the cervix is
generally considered unfavorable, and mechanical and/or pharmacological methods can
be used in this process.[16]
[51] Prostaglandins, including misoprostol, are contraindicated for cervical ripening
or induction of labor in full-term pregnancies with previous cesarean section or other
major uterine surgery due to the association with a higher risk of uterine rupture.[52] Pre-existing regular uterine activity is a relative contraindication to the use
of misoprostol, as it can lead to excessive uterine activity. Delaying or avoiding
administration should be considered if the patient has two or more painful contractions
within 10 minutes, especially in patients who have already received at least one dose
of prostaglandin.[53] In Brazil, misoprostol for vaginal use in labor induction is available in tablets
containing 25 mcg of the drug. The 50 mcg dose is more effective than the 25 mcg dose,
but leads to higher rates of tachysystole, cesarean delivery due to fetal compromise,
admission to neonatal intensive care units, and meconium elimination.[16]
[54] The interval between doses can vary between 3-6 hours. The number of doses required
for cervical maturation and/or effective labor varies. If necessary, oxytocin can
be started four hours after the final dose of misoprostol. There are no definitions
regarding the total limit of doses or the time of maturation and/or labor induction.[50]
[55]
[56] In some countries, a pessary with controlled release of misoprostol (200 mcg in
24 hours) is available. Comparative studies with the dinoprostone pessary have shown
a significantly shorter mean time to vaginal delivery and a greater chance of tachysystole.[57] A 2021 meta-analysis supported the use of low doses of oral misoprostol for labor
induction and suggested that an initial dose of 25 mcg can offer a good balance between
efficacy and safety.[14] Other routes for the use of misoprostol in labor induction, including buccal and
sublingual administration, have been less studied. Small trials suggest similar or
inferior results to those of vaginal or oral administration.[58]
[59]
[60] In pregnancies over 26 weeks, the use of misoprostol at an initial dose of 25 mcg
vaginally every 4-6 hours is recommended for cervical maturation prior to labor induction.
How to use misoprostol to induce labor in women with a previous cesarean section?
How to use misoprostol to induce labor in women with a previous cesarean section?
Women planning a vaginal birth after a previous caesarean section (Trial of labor
after cesarean – TOLAC) may need labor induction. There are two concerns: reduced
chances of vaginal birth after caesarean section (VBAC) and increased risk of uterine
rupture. Having a previous vaginal delivery and a favorable cervix are the main predictors
of induction resulting in VBAC.[61] Induction itself does not reduce the chances of VBAC when compared with expectant
management.[62] The major risk is uterine rupture related to induction. Regardless of the method
used for induction, women with a previous cesarean section and induced labor are at
greater risk of uterine rupture than those in labor with spontaneous delivery or expectant
management. The frequency of uterine rupture in women at full-term who had labor induced
was almost twice as high as the frequency in women in whom labor began spontaneously
(1.5% versus 0.8%).[63] The factors associated with an increased risk of rupture during induced TOLAC include:
-
No previous vaginal delivery – for example, in a study, the risks of rupture during
TOLAC-induced in women without a previous vaginal delivery versus a previous vaginal
delivery were 1.5% and 0.6%, respectively;[61]
[64]
-
Use of prostaglandins – induction with prostaglandins appears to be associated with
a greater risk of uterine rupture than induction with oxytocin or cervical ripening
with mechanical methods followed by administration of oxytocin.[64]
Risk of rupture with prostaglandin use – Data from large randomized trials and from good quality observational studies on
the effects of prostaglandins alone or in combination with other agents for cervical
ripening in TOLAC are not available. Much data on prostaglandin use in women with
a previous caesarean section has been derived from observational studies in which
misoprostol (PGE1) was used. Reports on the use of other prostaglandins, such as prostaglandin
E2, are limited by their small size, the co-administration of other agents and the
lack of stratification by previous vaginal delivery.[65]
Unspecified prostaglandin – Concern over the use of prostaglandins arose following the publication of a large
population-based retrospective cohort study that analyzed data from 20,095 primiparous
women who delivered after a single previous cesarean section.[65] In that study, the rate of uterine rupture was similar for women in spontaneous
labor and those induced without the use of prostaglandin, but significantly higher
among women induced with prostaglandin (type not available). The specific uterine
rupture rate by category was:
-
Repeat cesarean sections without labor: 1.6 ruptures per 1,000 planned repeat cesareans;
-
Spontaneous labor: 5.2 ruptures per 1,000 spontaneous deliveries;
-
Induced labor (without prostaglandins): 7.7 ruptures per 1,000 labors induced without
the use of prostaglandins;
-
Induced labor (with prostaglandins): 24.5 ruptures per 1,000 labors induced using
prostaglandins. Compared to repeat cesarean delivery, the relative risk of rupture
with the use of prostaglandins was 15.6 (95% CI: 8.1-30.0).
However, despite the very large number of cases, the information in this study is
from a database and individual reviews of medical records were not performed to check
other medications administered. The risk of uterine rupture reported in this retrospective
study was lower in another large prospective study.[66] In that study, the rate of uterine rupture among patients induced with prostaglandin
with or without oxytocin was lower – 14 per 1,000 induced deliveries –, although still
considerably high. Specifically on misoprostol (PGE1), a randomized trial on the use
of misoprostol for cervical ripening in labor induction in women with previous cesarean
sections was stopped early because of safety concerns due to uterine rupture.[67]
[68] This study and several case reports have led some researchers to conclude that misoprostol
is associated with a greater risk of uterine rupture than other prostaglandins and
therefore should not be used in women planning a TOLAC.[51]
[68]
[69]
[70]
[71] The positions of Gynecology and Obstetrics Societies worldwide are:
-
American College of Obstetricians and Gynecologists (ACOG –United States)[64] – advises that misoprostol should not be used for cervical ripening or labor induction
in women at term with any previous uterine incision and does not address the use of
prostaglandin E2;
-
Society of Obstetricians and Gynecologists of Canada (SOGC – Canada)[72] – has the same position regarding the use of misoprostol, but allows the use of
prostaglandin E2 (dinoprostone) in some circumstances and after appropriate advice;
-
National Institute for Health and Care Excellence (United Kingdom)[51] – concluded that if childbirth is indicated, women who have had a previous cesarean
section can receive labor induction with vaginal prostaglandin E2, but do not mention
misoprostol.[51]
[73]
In conclusion, the use of misoprostol in women with previous cesarean is not recommended
given the higher risk of uterine rupture. Note that mechanical methods are available,
effective and safe.
How to use misoprostol to induce labor in ruptured membranes?
How to use misoprostol to induce labor in ruptured membranes?
Premature rupture of membranes (PROM) is one of the most common complications of term
and preterm pregnancies, but there is a gap in knowledge about how management affects
the cesarean rate. As gestational age at delivery is the critical factor influencing
perinatal outcome, expectant management is generally adopted when far from term. In
PROM at term, the risk of maternal and fetal infectious morbidity increases with longer
duration of membrane rupture. Therefore, expectant management should be brief, with
instructions for induction of labor.[74] Meta-analyses conclude that misoprostol is an effective and safe agent for inducing
labor in women with PROM at term. Compared to oxytocin, the risk of contraction abnormalities
and the rate of maternal and neonatal complications were similar between the two groups.[74]
[75] Misoprostol 25 mcg should be considered as the starting dose for cervical ripening
and labor induction in women with PROM. The frequency of administration should not
exceed 3-6 hours. Furthermore, oxytocin should not be administered less than 4 hours
after the last dose of misoprostol. Misoprostol at higher doses (50 mcg every six
hours) may be appropriate in some situations, although higher doses may be associated
with an increased risk of complications, including uterine tachysystole with fetal
heart rate decelerations.[16] A Cochrane Review suggests the immediate induction of labor in patients with PROM
at term. Compared with expectant management, induction of labor is associated with
a reduction in maternal and possibly neonatal infection and lower treatment costs,
without an increase in cesarean sections.[76] In conclusion, the use of misoprostol is recommended as a safe and effective option
for women with PROM and unfavorable cervix, provided they do not have contraindications
for the use of this medication, such as, for example, previous cesarean section.
Misoprostol in the management of postpartum hemorrhage: how to use it?
Misoprostol in the management of postpartum hemorrhage: how to use it?
Postpartum hemorrhage affects around 2% of all patients, and in only 25% of cases
the risk factors are pronounced. The obstetrician must perform prophylaxis in 100%
of cases and be aware of the occurrence of PPH, even if drug prophylaxis is performed.
There is strong evidence that the association of uterotonics prescribed in the immediate
postoperative period of childbirth reduces blood loss greater than 500 mL: ergometrine
plus oxytocin (RR: 0.70; 95% CI: 0.59-0.84) and misoprostol plus oxytocin (RR: 0.70;
95% CI: 0.58-0.86) and reduces the need for blood products (RR: 0.51; 95% CI: 0.37-0.70).[77] This is not only a result of the combination of the strength of the two drugs, but
also because oxytocin is thermolabile and it is difficult to guarantee a cold chain
throughout the medication production, transportation and dispensing route. However,
the association of two uterotonics increases the occurrence of side events, mainly
vomiting (RR: 2.11; 95% CI: 1.39-3.18). Therefore, the use of two uterotonics is recommended
for patients at high risk of PPH, always bearing in mind the contraindication of ergometrine
for hypertensive/pre-eclampsia patients. The following uterotonics are recommended
for the prophylaxis of PPH:
Oxytocin:
-
In post-vaginal delivery: single dose of 10 IU intramuscularly right after birth;
-
In cesarean section: 5 IU in slow intravenous infusion in three minutes and maintenance
solution (20 IU of oxytocin in 500 ml of 0.9% saline solution intravenously at 125
ml/h for 4-12 hours);
-
Misoprostol: single dose of 600 mcg rectally;
-
Ergometrine: single dose of 0.2 mg intramuscularly.
For the drug treatment of PPH, the use of misoprostol 800 mcg rectally is recommended.
It is important to remember that since the onset of action of rectal misoprostol is
slower than that of other uterotonics, it should be used as an adjuvant to treatment
with oxytocin. Misoprostol should not be used in isolation, maintaining uterine massage
until the onset of its effect, which may take 15-20 minutes. Always consider the use
of tranexamic acid 1 g intravenously over 10 minutes, with the possibility of repeating
the 1 g dose in 30 minutes if bleeding persists.[78]
What regulations are related to the use of misoprostol?
What regulations are related to the use of misoprostol?
Circular letter number 182/2021 of the Office of the President of the Brazilian Federal
Council of Medicine,[79] expressed the impossibility of using misoprostol outside the hospital setting. The
letter highlights the Ordinance of the Brazilian National Health Surveillance Agency
(Anvisa) number 344/98,[80] of the Secretariat for Health Surveillance of the Ministry of Health, according
to which misoprostol is on list C1 that includes substances subject to special control
(prescription in two copies), with the addendum that the purchase and use of medication
containing the substance misoprostol will only be allowed in hospitals duly registered
with the Sanitary Authority. In its guide, the WHO (World Health Organization, 2018)[81] recognizes that the home use of misoprostol is a safe and effective option for women.
In addition, the drug was added to the WHO list of essential drugs in 2019, at the
same time that the need for in-person medical supervision to administer pharmacological
abortion was withdrawn. In Brazil, Anvisa ordinances and resolutions and manifestations
of the Federal Council of Medicine currently establish that misoprostol has exclusive
hospital use with special control. Compared to other countries in the world and to
WHO recommendations, there is excessive difficulty in accessing and releasing the
use of misoprostol in Brazil. Given the existence of a robust body of evidence, there
are no scientific justifications for imposing other restrictions on misoprostol, in
addition to those related to special control drugs, i.e. prescription in two copies
with retention of one copy in the pharmacy, and the possibility of identifying who
prescribed the induced abortion treatment.
Final considerations
In obstetric practice, misoprostol has been widely used in legal abortion, uterine
emptying due to embryonic or fetal death, cervical ripening and labor induction, and
management of PPH. Contrary to the accumulated scientific evidence, Brazil has one
of the most restrictive regulations in the world related to the use of misoprostol.
The great difficulty in acquiring, storing and dispensing the medication imposed by
Ordinance No. 344/1998 of Anvisa, still in force, contributes to denying the right
to safer outpatient treatments for women who need it. These restrictions also hinder
the availability of this medication, essential and mandatory, in obstetric care services.
National Commission Specialized in Childbirth, Puerperium and Abortion Care of the
Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)
President:
Alberto Trapani Júnior
Vice-President:
Alessandra Cristina Marcolin
Secretary
Sheila Koettker Silveira
Membros:
Elias Ferreira de Melo Junior
Liduina de Albuquerque Rocha e Sousa
Marcia Maria Auxiliadora de Aquino
Mirela Foresti Jiménez
Ricardo Porto Tedesco
Tenilson Amaral Oliveira
National Commission Specialized in Antenatal Care of the Brazilian Federation of Gynecology
and Obstetrics Associations (Febrasgo)
President:
Fernanda Garanhani de Castro Surita
Vice-President:
Lílian de Paiva Rodrigues Hsu
Secretary
Adriana Gomes Luz
Membros:
Jorge Oliveira Vaz
Eliana Martorano Amaral
Eugenia Glaucy Moura Ferreira
Francisco Herlanio Costa Carvalho
Joeline Maria Cleto Cerqueira
Jose Meirelles Filho
Luciana Silva dos Anjos França
Marianna Facchinetti Brock
Mary Uchiyama Nakamura
Patricia Goncalves Teixeira
Renato Ajeje
Sergio Hecker Luz
National Commission Specialized in Gestational Trophoblastic Disease of the Brazilian
Federation of Gynecology and Obstetrics Associations (Febrasgo)
President:
Antonio Rodrigues Braga Neto
Vice-President:
José Mauro Madi
Secretário
Mauricio Guilherme Campos Viggiano
Membros:
Bruno Maurizio Grillo
Christiani Bisinoto de Sousa
Claudio Sergio Medeiros Paiva
Elaine Azevedo Soares Leal
Elza Maria Hartmann Uberti
Fabiana Rebelo Pereira Costa
Izildinha Maesta
Jose Arimatea dos Santos Junior
Maria do Carmo Lopes de Melo
Rita de Cassia Alves Ferreira Silva
Sue Yazaki Sun
Tiago Pedromonico Arrym
National Commission Specialized in High Risk Pregnancy of the Brazilian Federation
of Gynecology and Obstetrics Associations (Febrasgo)
President:
Rosiane Mattar
Vice-President:
Alberto Carlos Moreno Zaconeta
Secretary
Mylene Martins Lavado
Membros:
Arlley Cleverson Belo da Silva
Carlos Alberto Maganha
Elton Carlos Ferreira
Felipe Favorette Campanharo
Inessa Beraldo de Andrade Bonomi
Janete Vettorazzi
Maria Rita de Figueiredo Lemos Bortolotto
Fernanda Santos Grossi
Renato Teixeira Souza
Sara Toassa Gomes Solha
Vera Therezinha Medeiros Borges
National Commission Specialized in Fetal Medicine of the Brazilian Federation of Gynecology
and Obstetrics Associations (Febrasgo)
President:
Mario Henrique Burlacchini de Carvalho
Vice-President:
José Antonio de Azevedo Magalhães
Secretary
Roseli Mieko Yamamoto Nomura
Membros:
Alberto Borges Peixoto
Carlos Henrique Mascarenhas Silva
Carolina Leite Drummond
Edward Araujo Júnior
Fernando Artur Carvalho Bastos
Guilherme Loureiro Fernandes
Jair Roberto da Silva Braga
Jorge Fonte de Rezende Filho
Marcello Braga Viggiano
Maria de Lourdes Brizot
Nadia Stella Viegas dos Reis
Reginaldo Antônio de Oliveira Freitas Júnior
Rodrigo Ruano
National Commission Specialized in Maternal Mortality of the Brazilian Federation
of Gynecology and Obstetrics Associations (Febrasgo)
President:
Marcos Nakamura Pereira
Vice-President:
Rodolfo de Carvalho Pacagnella
Secretary
Melania Maria Ramos de Amorim
Membros:
Acacia Maria Lourenço Francisco Nasr
Douglas Bernal Tiago
Elvira Maria Mafaldo Soares
Fatima Cristina Cunha Penso
Ida Perea Monteiro
João Paulo Dias de Souza
Lucila Nagata
Maria do Carmo Leal
Monica Almeida Neri
Monica Iassanã dos Reis
Jacinta Pereira Matias
Penha Maria Mendes da Rocha
National Commission Specialized in Obstetric Emergencies of the Brazilian Federation
of Gynecology and Obstetrics Associations (Febrasgo)
President:
Alvaro Luiz Lage Alves
Vice-President:
Gabriel Costa Osanan
Secretary
Samira El Maerrawi Tebecherane Haddad
Membros:
Adriana Amorim Francisco
Alexandre Massao Nozaki
Brena Carvalho Pinto de Melo
Breno José Acauan Filho
Carla Betina Andreucci Polido
Eduardo Cordioli
Frederico Jose Amedee Peret
Gilberto Nagahama
Laises Braga Vieira
Lucas Barbosa da Silva
Marcelo Guimarães Rodrigues
Rodrigo Dias Nunes
Roxana Knobel
National Commission Specialized in Sexual Violence and Pregnancy Interruption Provided
for by Law of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)
President:
Robinson Dias de Medeiros
Vice-President:
Cristião Fernando Rosas
Secretary
Helena Borges Martins da Silva Paro
Membros:
Aline Veras Morais Brilhante
Anibal Eusébio Faúndes Latham
Débora Fernandes Britto
Edison Luiz Almeida Tizzot
Isabelle Cantidio Fernandes Diogenes
Kenia Zimmerer Vieira
Michele Lopes Pedrosa
Osmar Ribeiro Colas
Rivaldo Mendes de Albuquerque
Rosires Pereira de Andrade
Suely de Souza Resende
Zelia Maria Campos
National Commission Specialized in Professional Defense and Appreciation of the Brazilian
Federation of Gynecology and Obstetrics Associations (Febrasgo)
President:
Maria Celeste Osorio Wender
Membros:
Carlos Henrique Mascarenhas Silva
Etelvino de Souza Trindade
Henrique Zacharias Borges Filho
Juvenal Barreto Borriello de Andrade
Lia Cruz Vaz da Costa Damásio
Maria Rita de Souza Mesquita
Mirela Foresti Jiménez
Sergio Hofmeister de Almeida Martins Costa
Celia Regina da Silva
Aljerry Dias do Rego
Rosires Pereira de Andrade
Maria Auxiliadora Budib
Carlos Alberto Sa Marques
Hilka Flavia Barra do Espirito Santo Alves Pereira
