Recent Advances in Obstetrics and Gynecology—7 S Dasgupta
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SECTION 1
OBSTETRICS

Misoprostol in ObstetricsOne

Jaswinder Kalra,
Sarala Gopalan
Prostaglandins have been found to be involved in every stage of human reproduction ever since their discovery in 1935. In 1970s, the researchers found that prostaglandin analogs with more selective action on myometrium could be used to induce abortion in early pregnancy; however, these caused a high rate of gastrointestinal side effects and often lacked stability for long-term storage. It was in 1985 that researchers reported the effectiveness of prostaglandin analogs as an abortifacient when used along with mifepristone with lower doses and fewer adverse effects (Bygdeman and Swahn). Misoprostol is one such prostaglandin analog of PGE1 which is clinically useful as an orally administered drug, being cheap and stable unlike the other closely related prostaglandins used in obstetrical practice such as dinoprostone (PGE2), carboprost (15-methyl-PGF2α), gemeprost (PGE1) and sulprostone (PGE2 analog). Although misoprostol has been approved by the Food and Drug Administration (FDA) solely to be taken orally for the prevention and treatment of gastric ulcers when associated with the use of nonsteroidal anti-inflammatory drugs, it has also become an important drug in obstetrical and gynecologic practice because of its uterotonic and cervical ripening actions. Misoprostol is not approved by the US-FDA for use alone in any of the obstetric and gynecological indications as yet; however, the FDA recognizes that in certain circumstances, off-label uses of approved products are appropriate, rational and accepted medical practice and not considered experimental if based scientific evidence (Rayburn, 1993).
 
PHARMACOKINETICS, PHYSIOLOGY AND TERATOGENICITY
Misoprostol is manufactured as oral tablets as 100 and 200 μg scored tablets which can be used through oral, sublingual, vaginal and rectal route. Misoprostol, which is synthetic PGE1 analog has been made orally stable with reduced side effects and long shelf-life by bringing about an alteration in the chemical structure of the naturally occuring parent compound.
 
Oral Route
After oral administration, misoprostol is rapidly absorbed and converted to its pharmacologically active metabolite, misoprostol acid, less than 90 percent of 2which remains bound to serum protein. Following oral administration, the plasma concentrations of misoprostol acid peak in approximately 30 minutes with a rapid decline therafter with a half-life of 21 minutes (Zieman et al, 1997). The bioavailability of misoprostol is decreased by concomitant ingestion of food or antacids. Misoprostol is mainly metabolized in liver with less than 1 percent of its active metabolite excreted in urine (Foote et al, 1995). Therefore, dose of the drug needs to be adjusted when used in patients with liver disease, whereas no dose adjustment is required for patients with renal insufficiency who do not require dialysis. Misoprostol does not induce hepatic cytochrome P-450 enzyme system and has no known drug interactions.
 
Vaginal Route
Vaginal administration of misoprostol is associated with increased reproductive tract effects and reduced gastrointestinal effects (Danielsson et al, 1999 and Toppozada et al, 1997). When misoprostol tablet is placed in posterior fornix of vagina, plasma concentration of misoprostol acid peaks in 1 to 2 hours and then declines slowly (Zieman et al, 1997). Although vaginal application of misoprostol is associated with slower increases and lower peak plasma concentrations of misoprostol acid than does oral administration, however, overall exposure to the drug is increased.
 
Comparison between Different Routes
In a comparison between oral and vaginal administration of misoprostol of uterine contractility when given prior to surgical evacuation to women with 9 to 11 weeks of pregnancy, Danielsson et al (1999) observed an increase in intrauterine pressure beginning 8 minutes after oral administration with a peak at 25 minutes. When given vaginally, intrauterine pressure showed increase at 21 minutes with a peak at 46 minutes. Uterine contractility plateaued at one hour after oral administration, whereas uterine contractility increased continuously for 4 hours after vaginal application thus showing a significantly higher maximal contractility with vaginal administration. Sublingual route of administration was found to have a greater overall exposure to the drug when compared to oral and vaginal route but similar to vaginal route when the tablet was administered vaginally moistened with water (Tang et al, 2002).
 
Adverse Effects
The most common adverse effects of misoprostol are nausea, vomiting, diarrhea, abdominal pain, chills, shivering and fever and all these are dose dependent. Unlike Prostaglandin E2 and Prostaglandin F2α, misoprostol is not known to cause myocardial infarction or bronchospasm. Although toxic doses of misoprostol are yet to be determined; cumulative doses of up to 2200 μg given 3over a period of 12 hours have been well tolerated by pregnant women with no serious side effects (El-Rafaey H and Templeton, 1995).
 
Teratogenecity
A syndrome of congenital facial paralysis (Mobius'syndrome) has been reported in infants of women who have taken misoprostol during first trimester in an unsuccessful attempt to induce abortion (Pastuszak et al, 1998 and Gonzalez et al, 1998). In a more recent Latin American study, an increased frequency of transverse limb defects, ring-shaped constrictions of the extremities, arthrogryposis, hydrocephalus, holoprosencephaly and exostrophy of bladder, but not Mobius’ syndrome has been noted (Orioli and Castilla, 2000).
 
MISOPROSTOL IN FIRST TRIMESTER TERMINATION OF PREGNANCY
Misoprostol has been used most extensively in conjunction with either mifepristone or methotrexate for first trimester medical abortion with both regimens found to be equally effective.
 
Mifepristone + Misoprostol
In the initial studies, misoprostol was given only orally in combination with mifepristone resulting in a complete abortion rate of 91 to 97 percent in up to 49 days of pregnancy with an oral mifepristone 600 μg followed 48 hours later by 400 μg of oral misoprostol (WHO Task Force 2000, Peyron et al, 1993; Spitz et al, 1998, and Winikoff et al, 1977). The success rate was 83 to 95 percent in women with 56 days of gestation. Lowering the dose of mifepristone to 200 μg did not lower the efficacy; whereas reducing the dose of mifepristone to 200 μg and increasing the dose of oral misoprostol to 600 μg resulted in complete abortion rate of 96 to 97 percent in women with up to 49 days of gestation and 89 to 93 percent in those up to 63 days (Winikoff et al, 1977; Mckinley et al, 1993 and Baird et al, 1995).
When misoprostol was given vaginally for medical first trimester abortion in combination with mifepristone in same doses, it was found to be more effective. A single oral dose of 600 μg mifepristone followed 48 hours later by 800 μg of vaginal misoprostol resulted in complete abortion in 95 to 98 percent of women with up to 63 days of pregnancy (El-Rafaey et al, 1995 and Schaff et al, 1997). Ninety-three percent of the complete abortions occurred within 4 hours of taking misoprostol. Similar results in efficacy were also seen with reduced dose of mifepristone (200 μg) in women with both up to 56 days and 63 days of gestation (Ashok et al, 1998 and Schaff et al, 1999 and 2000). The same regimen of misoprostol has been used successfully by women at home after 1 to 3 days of receiving mifepristone. Although a combined regimen of mifepristone and misoprostol has been found to result in complete abortion in 94 to 95 percent of women with 9 to 13 weeks of pregnancy, the incidence of 4heavy vaginal bleeding in this group of women is found to be much more (Ashok et al, 1998 and Gouk et al, 1999).
 
Methotrexate + Misoprostol
As an alternative to mifepristone, methotrexate in a single dose of either oral or intramuscular dose has been combined with misoprostol for first trimester termination of pregnancy. Methotrexate (50 mg per square meter of body surface area) followed 5 to 7 days later by vaginal misoprostol (800 μg) resulted in a complete abortion in 88 to 100 percent of women (Creinin et al, 1995 and 1996; Carbonell et al, 1998 and 1999, and Hausknecht, 1995). The abortion occurred within 24 hours after one dose of misoprostol in 53 to 60 percent of women and among the rest 19 to 32 percent aborted within 24 hours after the second dose of misoprostol. The abortion was completed in 24 to 28 days in those who had a delayed response to methotrexate and misoprostol. A multicentric randomized trial comparing methotrexate with mifepristone revealed that abortions induced with mifepristone were complete faster than those induced with methotrexate; however, the overall success rate, side effects and complications were similar in both groups (Weibe et al, 2002).
The majority of studies of medical abortions in the first trimester with mifepristone or methotrexate plus misoprostol have included women with gestation of less than 63 days. Complete abortion rates in women less than 49 days’ pregnancy are higher than those with pregnancy of greater duration (Spitz et al, 1998; McKinley et al, 1993; Baird et al, 1995, and Creinin et al, 1996).
 
Use of Misoprostol-Alone
The current evidence on the efficacy of potential regimens for early abortion using misoprostol-alone is hard to interpret. The earliest studies of misoprostolinduced abortion in the first trimester reported complete abortion rates of 5 to 11 percent with a total dose of 400 μg of oral misoprostol (Weibe et al, 2002 and Norman et al, 1991). Complete abortion rates of up to 96 percent were observed in women with up to 63 days of pregnancy when three doses of 800 μg of vaginal misoprostol were given every 48 hours (Carbonell et al, 1997). In a randomized trial comparing methotrexate plus vaginal misoprostol and vaginal misoprostol-alone only 47 percent of women given misoprostol-alone had complete abortions, as compared with 90 percent of those women given methotrexate plus misoprostol (Creinin and Vittinghoff, 1994). Moistening of the misoprostol tablets has failed to show a significant difference in the rates of complete abortion when compared in randomized trials using misoprostol-alone and in combination with mifepristone or methotrexate (Ngai et al, 2000 and Creinin et al, 1999).
Counseling and education is an important factor in medical abortion and influences the success and patient satisfaction to a larger extent. The woman's 5decision to have an abortion needs to be confirmed and the gestational age of the pregnancy should be estimated. Key points needed to be discussed are summarized in Table 1.1.
Table 1.1   Key points to discuss prior to medical abortion
  1. Compare the risks and benefits of medical and surgical abortion alternatives.
  2. Review the known side effects of the drugs used for medical abortion.
  3. Discuss the potential teratogenicity of the drugs emphasizing that once administered the abortion should be completed either medically or surgically.
  4. Discuss the risks of continuing pregnancy, incomplete abortion and hemorrhage necessitating surgical evacuation.
  5. Clarify that the process is a lengthy one and may need multiple office visits.
  6. Discuss the amount of pain associated with procedure which may need medication and possible heavy bleeding with the passage of products of conception.
  7. Issues of confidentiality and social and physical support need to be addressed.
  8. Future contraception needs to be discussed.
  9. Emergency contact numbers and urgent hospitalization facility should be available.
The FDA-labeled contraindications of the drug include—allergy to any of the medications used, i.e. mifepristone and misoprostol, chronic use of systemic corticosteroids, chronic adrenal failure, inherited porphyrias, coagulopathy or suspected ectopic pregnancy or undiagnosed adnexal mass. It is also recommended that women who do not have access to a medical facility should not have a medical abortion.
 
Standard Regimen
After confirming the eligibility to undergo medical abortion 600 mg of mifepristone is administered orally on day 1. On day 3, the patient is assessed for possibility of pregnancy expulsion which can occur in 2 to 3 percent of patient with mifepristone-alone (Peyron et al, 1993 and Spitz et al, 1998). If abortion has not occurred 48 hours after mifepristone, 400 μg of misoprostol is administered orally as a single dose and the patient is observed at the clinic for 4 hours. A follow-up visit at day 15 is scheduled to confirm clinically or by sonography that complete abortion has occurred. Treatment success is determined by the avoidance of surgical evacuation.
Since failure includes indications for surgical intervention and not only drug failure for the same gestational age, a relative lower success rate in some US trials has been attributed to the lack of experience of the investigators and an increased dependence on ultrasonography (Newhall and Winikoff, 2000). Success rates of some recent trials are shown in Table 1.2.
In order to decrease the cost of medical abortion, studies have carried out to attempt to reduce the dose of mifepristone used with misoprostol. Three doses of mifepristone—200, 400 and 600 mg were compared in a trial reported by the World Health Organization Task Force on Postovulatory Methods of Fertility Regulation (1993).
6
Table 1.2  
Reference
No of patients
Gestational age
Success %
Ongoing pregnancy %
1. Ulmann et al, 1992
1,211
< 49
95.3
0.2
2. Peyron et al, 1993
488
< 49
96.9
0.8
3. Aubeny et al, 1995
1,108
< 49
94.8
1.4
< 56
93.4
1.6
4. Spitz et al, 1998
2,015
< 49
92
1.0
< 56
83
4.0
5. Winikoff et al, 1997
250
< 56
94.8
–
6. Kahn et al, 2000
Meta-analysis of 54 studies
< 49
94-96
1-3
Complete abortion rates (93.8%, 94.1% and 94.3%) and overall continuing pregnancy rates (0.4%) were found to be no different among the three groups. Subsequently, two large trials have confirmed the efficacy of 200 mg of mifepristone with misoprostol (Schaff et al, 1999 and WHO Task Force 2001). In an attempt to further reduce the dose of mifepristone to 50 mg resulted in a relative risk of 1.6 failure as compared to a higher dose (WHO Task Force, 2001 and Creinin et al, 2001).
 
Vaginal Misoprostol Versus Oral Misoprostol for Early Abortion
A randomized trial by El-Refaey et al (1995) comparing 80 μg misoprostol administered vaginally versus orally found a significantly increased rate of abortion within 4 hours of vaginal dose (93% vs.78%) an ongoing pregnancy rate of 1 percent vs. 7 percent and a similar incomplete abortion rate in the two groups. The incidence of vomiting (31% vs. 44%) and diarrhea (18% vs. 36%) were significantly lower in the vaginal groups. Three large studies using low dose mifepristone drug with vaginal misoprostol in gestation between 50 and 63 days have shown success rates of 96-98 percent (Schaff et al, 1999 and 2000, and WHO Task Force 2001).
 
Varying Interval between Mifepristone and Misoprostol
Vaginal misoprostol when administered from 2 to 3 days post mifepristone has been found to be equally effective when compared to the conventional 48 hours interval (Schaff et al, 2000). In another trial attempting misoprostol administration on the same day, 6 to 8 hours after mifepristone was not found to be as effective as the standard regimen (Creinin et al, 2001).
 
MISOPROSTOL FOR FAILED EARLY PREGNANCY
7In missed abortion or an embryonic pregnancy, the trophoblastic activity has already declined and the physiological changes that lead to spontaneous expulsion are underway. Misoprostol can be used to evacuate the uterus medically without the prior use of mifepristone thus reducing the cost of medical treatment for missed abortions (Gronlund et al, 2002). In a study by Creinin et al (1997) comparison was made between 400 μg oral misoprostol and 800 μg vaginal misoprostol for medical evacuation of early failed pregnancy with an embryo of 5 to 14 mm with no cardiac activity or an empty irregular gestational sac of at least 16 mm in diameter. The doses were repeated after 24 hours in case of failure of expulsion. The rate of complete expulsion within 48 hours was 25 percent in oral misoprostol and 88 percent in vaginal misoprostol group. Similar efficacy was also shown by other authors as well (Zalanyi, 1998 and Heraboutya et al, 1997).
Misoprostol has also been used for completing an inevitable or incomplete abortion. In an initial report, 95 percent success was obtained with 400 μg of oral misoprostol in such cases (Henshaw et al, 1993). There is no consensus on the ideal dosage schedule at present. Three sequential doses of oral 200 μg misoprostol were found to be successful in 85 percent cases (Pandian et al, 2001). Similar results were seen with vaginal misoprostol given sequentially on alternate days for 3 doses in another study (Ngai et al, 2001). However, in a randomized study (deJonge et al, 1995) of 50 women with inevitable abortion with bleeding and dilated cervical os and a uterine size of less than 14 weeks, patients either were given a single dose of 400 μg oral misoprostol or underwent immediate surgical evacuation. Surgery was significantly more successful than misoprostol in completing the abortion in 12 hours (97% vs 13%). The mean hemoglobin concentration fell significantly in women in the misoprostol group. Therefore, misoprostol is currently not recommended for treatment of inevitable and incomplete abortion.
 
MISOPROSTOL FOR CERVICAL RIPENING BEFORE SURGICAL ABORTION
Cervical ripening is the softening, effacement and gradual dilatation of the cervical os and is helpful in reducing the incidence of cervical laceration and uterine perforation at the time of abortion (Grimes et al, 1984 and Schulz et al, 1983). It can be accomplished with the use of either hydrophilic dilator (e.g. Laminaria, Hypan and Dilapan) or biochemical agents such as prostaglandins and nitric oxide donors. Misoprostol has been studies extensively as cervical ripening agent before surgical termination of pregnancy and is an attractive option being less expensive, more easily stored and fewer side effects (El-Rafaey et al, 1994 and Maclssac et al, 1999). Vaginal misoprostol in the dose of 400 μg was found to be more effective than oral misoprostol and equivalent to one medium laminaria used 4 hours prior to surgical evacuation. However, laminaria placement was found to be more painful. In another randomized 8study of 120 women, comparison was between 200 μg, 400 μg, 600 μg and 800 μg of misoprostol given vaginally 3 to 4 hours before suction curettage (Singh et al 1998). Only 23 percent of women given the 200 μg dose had cervical dilatation of at least 8 mm compared to 97%, 100% and 100% of women given 400 μg, 600 μg and 800 μg respectively. There were significantly more adverse effect with 600 μg and 800 μg doses and therefore 400 μg dose of vaginal misoprostol is recommended for cervical ripening. The optimum length of time required for cervical ripening was found to be 3 to 4 hours before suction curettage as giving the dose only 2 hours before the procedure was less effective in obtaining adequate cervical dilatation (Singh et al, 1999).
 
MISOPROSTOL IN THE SECOND TRIMESTER OF PREGNANCY
Evacuation of uterus in the second trimester of pregnancy may be required because of maternal medical problems, fetal death, fetal major congenital abnormalities or for unwanted pregnancy. Such abortions when performed during this gestational period require significant cervical dilatation before extraction of fetus or induction of labor. Several studies have evaluated the use of misoprostol for termination of a second trimester pregnancy; however, the comparison of their studies is difficult as they have included women with pregnancies of widely varying duration. The dose of a uterotonic agent required early in second trimester is more compared to the one required in late second trimester as the uterus becomes more sensitive with increasing gestational age. In addition, the presence of a dead fetus and duration of pregnancy after fetal death influences both the rate of successful induction of labor and the time from induction to delivery. Similarly, various studies have used different definitions of successful abortion and have used a wide range of additional interventions.
The optimal dose of vaginal misoprostol for induction of labor in second trimester probably lies somewhere between 50 μg and 800 μg. Higher doses may be required within this range for early second trimester abortion, whereas lower dose may be adequate for later in second trimester. The rate of successful abortion (delivery of fetus within 48 hours) has been reported to vary from 71 to 100 percent with 200 μg misoprostol given vaginally every 12 hours (Jain et al, 1999; Nuutila et al, 1997; Herbutya et al, 1998 and Bugalho et al, 1993). Dosing of misoprostol every 6 hours was found to be no more effective than 12 hours although increasing the frequency of dose was expected to increase the efficacy.
Wong et al (1998) in a randomized trial of 400 μg of vaginal misoprostol and gemeprost given every 3 hours found 91 percent complete abortion rate in 48 hours in women undergoing induction of labor in second trimester. In another study (Herbutya et al, 1998) vaginal doses of 200 μg, 400 μg and 600 μg given every 12 hours to women in second trimester resulted in abortions in 71, 82 and 96 cases, 9respectively. However, higher doses were associated with a higher rate of adverse effects such as fever (0%, 2% and 28% respectively), nausea and vomiting (4%, 12% and 20%) and diarrhoea (0%, 6% and 22%). More recent studies have found similar results to the earlier studies using 200 μg, 400 μg, 600 μg, and 800 μg vaginal misoprostol (Herbutya et at, 2001 and Pongsatha et al, 2001). Although the optimal regimen has not been determined, it appears that 200 to 600 μg of misoprostol given vaginally every 12 hours or 400 μg given vaginally every 3 hours is successful in inducing labor in second trimester (Dickenson and Evans, 2002). Use of prior mifepristone (36 to 48 hours) makes the induction of labor in second trimester with misoprostol more successful (90 to 97%) as shown by El-Rafaey (1995), Webster et al (1996) and Ho et al (1996).
Uterine rupture has been reported in women undergoing abortion in the second trimester with misoprostol, both in previously scarred uterus and unscarred uterus (Phillips et al, 1996 and Chen et al, 1999). The risk of uterine rupture associated with induction of labor with misoprostol in the second trimester of pregnancy however is unknown, as nearly all such trials of misoprostol have excluded women with uterine scars.
 
MISOPROSTOL IN THE THIRD TRIMESTER OF PREGNANCY
 
Induction of Labor with a Viable Fetus
Several clinical trials have evaluated misoprostol for induction of labor at term comparing it with placebo (Fletcher et al, 1993 and Ngai et al, 1996) oxytocin (Kramer et al, Sanchez-Ramos et al, 1997) and other prostaglandins such as prostaglandin E2 gel (Wing et al 1995, 1997, 1998; Varaklis et al, 1995; Buser et al, 1997; Gottschall et al, 1997 and Kolder up et al, 1999) or vaginal insert (Sanchez-Ramos et al, 1998 and Wing et al, 1997). When used as a cervical ripening agent before induction of labor, both oral and vaginal misoprostol has been found to be more effective than a placebo. Misoprostol has also been found to be an effective agent for induction of labor. Misoprostol was found to have a shorter induction of labor to delivery interval by 4.6 hours and a lower cesarean delivery rate in a meta-analysis of randomized, controlled trials evaluating cervical ripening and labor induction in a total of 488 women given misoprostol and 478 controls who mostly received prostaglandin E2 gel (Sanchez-Ramos et al, 1997).
Several additional randomized, controlled trials have been completed on the use of misoprostol for induction of labor and its comparison with other methods. Additionally, this drug has been administered by different routes for labor induction (vaginal, oral and sublingual) and with different doses at varying intervals; therefore, the reported success rates and adverse effects are also variable. In a Cochrane Review (Alfirevic et al, 2003) oral misoprostol was found to reduce the need for oxytocin infusion from 51 to 13 percent (relative risk 0.25, 95% confidence interval 0.1 to 0.6) and shortened delivery time by 8.7 hours when used for induction of labor in women with term prelabor rupture to membranes. When compared with vaginal or intracervical prostaglandins, oral misoprostol showed no beneficial or harmful effects. In 10seven trials with 1,278 randomized women that compared oral with vaginal misoprostol, oral misoprostol appeared to be less effective. More women in the oral misoprostol group did not achieve vaginal delivery within 24 hours of randomization (50%) compared with 39.7 percent in the vaginal misoprostol group (relative risk 1.27, 95 percent confidence interval 1.09 to 1.47). The cesarean section rate was lower in the oral misoprostol group (16.7%) compared with 21.7 percent in the vaginal misoprostol group (relative risk 0.77, 95% confidence interval 0.61 to 0.97). There was no difference in uterine hyperstimulation with fetal heart rate changes (8.5% versus 7.4%). There were no reported cases of severe neonatal and maternal morbidity.
In a Cochrane review including 62 trials on vaginal misoprostol for cervical ripening and induction of labor compared to placebo, vaginal misoprostol was found to be associated with increased cervical ripening (relative risk of unfavorable cervix after12 to 24 hours with misoprostol was 0.09, 95% confidence interval 0.03 to 0.24) (Hofmeyer et al, 2003). It was also associated with reduced failure to achieve vaginal delivery within 24 hours (relative risk 0.36, 95% confidence interal 0.19 to 0.68). Uterine hyperstimulation without fetal heart rate changes was increased (relative risk 11.7, 95% CI 2.78 to 49). Compared with vaginal prostaglandin E2, intracervical prostaglandin E2 and oxytocin, vaginal misoprostol labor induction was associated with less epidural analgesia use, fewer failures to achieve vaginal delivery within 24 hours and more uterine hyperstimulation. Compared with prostaglandin E2 gel, oxytocin augmentation was less common with vaginal misoprostol and meconium-stained liquor was more common. Whether the increased incidence of meconiumstained liquor was due to increased incidence of fetal distress in misoprostol group or due to direct effect of misoprostol on fetal gastrointestinal tract is unknown.
Lower doses of misoprostol compared to higher doses were associated with more need for oxytocin augmentation, less uterine hyperstimulation with and without fetal heart rate changes and a non-significant trend to fewer admissions to neonatal intensive care unit. However, because there were so few serious adverse effects, the relative risk of rare adverse outcomes with the use of misoprostol for induction of labor remains unknown.
Sublingual route of misoprostol has also been evaluated for induction of labor at term in a randomized control trial in 250 women with the objective of comparing its efficacy, side effects and acceptability with oral misoprostol (Shetty et al, 2002). In this study 50 μg of sublingual misoprostol given 4 hourly was found to have similar efficacy and safety profile as compared to 100 μg oral misoprostol; however, oral misoprostol was found to be more acceptable to women.
In an effort to find an effective dose of misoprostol that does not increase the frequency of uterine hyperstimulation, some recent studies have focused on low dose regimens of misoprostol. In a study of 522 women given 25 μg of vaginal misoprostol every three hours (up to 8 doses) or 25 μg every 6 hours (up to 4 doses). The latter regimen resulted in longer time to delivery 11and greater need for augmentation with oxytocin. However, the rates of uterine hyperstimulation with fetal heart rate changes, meconium passage, the rate of cesarean delivery and neonatal effects (Apgar scores, admission to neonatal intensive care unit and meconium passage) were similar in the two treatment groups, other lower dose regimens which include less dose at fixed intervals (25 μg 6 hourly versus 3 hourly) have been found to be equally effective although with increased need for oxytocin augmentation and less chance of uterine hyperstimulation (Shetty et al, 2002; Hofmeyer et al, 1999 and Sanchez-Ramos et al, 2002). The available data suggest that the best dose of misoprostol for induction of labor is 25 μg given vaginally every 4 to 6 hours.
 
Induction of Labor with Fetal Death
Misoprostol is an attractive agent for induction of labor after fetal death in the third trimester because there is no concern about its adverse effects of uterine hyperstimulation on the fetus. Misoprostol 50 μg to 100 μg can be given vaginally 12 hourly, with the lower being more suitable for fetal death closer to term and higher dose for early 3rd trimester fetal death. A dose of 100 μg of vaginal misoprostol given 12 hourly resulted in nearly 100 percent rate (Bugalho et al, 1994 and 1995).
 
Induction of Labor in Women with Previous Cesarean Delivery
There have been several reports of uterine rupture with the use of misoprostol for induction of labor in women attempting vaginal delivery after cesarean section (Bennett 1997, Wing et al, 1998, and Plaut 1999). A randomized trial comparing 25 μg misoprostol vaginally every 6 hours with oxytocin for induction of labor in women with previous one cesarean delivery was terminated after uterine scar disruptions in two women in misoprostol group (Wing et al, 1998). In another case-control study, 5.6 percent of women in misoprostol group had symptomatic uterine scar rupture as compared to 0.2 percent in women undergoing trial of labor without administration of misoprostol, with none occurring in those with spontaneous labor (Plaut et al 1999). It remains unclear whether the use of misoprostol per se increases the frequency of uterine scar rupture or whether any drug used to induce labor with unfavorable cervix increases the risk of scar rupture. Rupture of uterus has also been reported in a primigravida (Thomas et al, 2003) as well as multigravida (Mathew et al, 2000) without a previously scarred uterus indicating that the drug must be used with great caution for induction of labor. However, until it has been proved safe, misoprostol should not be used to induce labor in women with uterine scars.
 
MISOPROSTOL FOR POSTPARTUM HEMORRHAGE
Misoprostol because of its uterotonic properties has been evaluated for prevention as well as treatment of postpartum hemorrhage. In an earlier 12prospective observational study 600 μg of misoprostol given orally just after clamping of umbilical cord was associated with blood loss of 500 ml or more in 6 percent of women with none of them having had blood loss of 1000 ml or more (El-Rafaey et al 1997). However, more recently, three randomized trials involving over 1000 women evaluated the efficacy of misoprostol (400 μg rectally or 400 to 600 μg orally) for preventing postpartum hemorrhage. The frequency of postpartum hemorrhage (blood loss > 1000 ml) was not found to be lower in misoprostol group (Bamigboye et al, 1998; Hofmeyr et al, 1998 and Surbek et al, 1999). Another study observed that rectal misoprostol is significantly less effective than oxytocin and ergometrine for prevention of postpartum hemorrhage (Calisken et al, 2002). The World Health Organization (WHO) has completed a study of 20,000 women in nine countries to evaluate the effec-tiveness of oral misoprostol in preventing severe postpartum hemorrhage. Women receiving misoprostol were found to have a higher rate of blood loss of 1000 ml of more compared to those who received oxytocin (4% versus 3%) and required additional uterotonics more frequently (Gulmezoglu et al, 2001). In a recent Cochrane review (Mousa et al, 2003) on treatment of primary postpartum hemorrhage a rectal misoprostol in a dose of 800 μg has been suggested as a possible useful first-line drug; however, further randomized controlled trials are required to arrive at any consensus and at present misoprostol is not yet approved for prevention or treatment of postpartum hemorrhage.
Misoprostol regimens for various indications in obstetric practice are shown in Table 1.3.
Table 1.3   Misoprostol—regimens for pregnant women
Indication
Recommended regimen
Medical abortion
(at<56 days of gestation)
 Mifepristone and misoprostol
200 mg of oral mifepristone followed 36-48 hr later by 800 μg of vaginal misoprostol
 Methotrexate and misoprostol
50 mg of intramuscular or oral methotexate per square meter of body surface area, followed 5-7 days later by 800 μg of vaginal misoprostol (repeat misoprostol dose 24 hr later if necessary).
 Misoprostol alone
Insufficient evidence to recommend
Incomplete spontaneous abortion
(cervix open bleeding)
Insufficient evidence to recommend
Missed abortion (cervix closed; embryo 5-14 mm with no cardiac activity or empty, irregular gestational sac ≥ 16 mm in diameter)
800 μg of vaginal misoprostol (repeat once 24 hr later if necessary) or 200 μg necessary) or 200 μg of vaginal misoprostol given every 4 hr.
Preoperative cervical ripening
First trimester
400 μg of vag.misoprostol 3-4 hr before suction curettage
13
Second trimester
Insufficient evidence to recommend
Induction of labor in the second trimester
200 μg of oral mifepristone, followed 36-48 hr later by 600 μg of vaginal misoprostol and then by 400 μg of oral or vaginal misoprostol every 3 hr (a maximum of five doses)
  or
200-600 μg of vaginal misoprostol every 12 hr
  or
400 μg of vaginal misoprostol every 3 hr (a maximum of five doses)
Induction to labor in the third trimester
Viable fetus
25 μg of vaginal misoprostol every 4-6 hr
Fetal death
100 μg of vaginal misoprostol 12 hr
Vaginal birth cesarean delivery
Contraindicated
Postpartum hemorrhage
Prevention
400-600 μg of misoprostol given orally or rectally after delivery of the neonate but before delivery of the placenta (if other uterotonic agent is not available)
Treatment
1000 μg of misoprostol given rectally if treatment with oxytocin and methylergonovine is unsuccessful and if prostaglandin F2α is not available
 
CONCLUSION
Misoprostol has been extensively studied for its use in obstetrics and has been found to be one of the most important medications. Data from clincial trials provide strong and consistent support for use of misoprostol as part of medical abortion regimens in the first trimester. There is also strong and consistent evidence to support the use of misoprostol for cervical ripening before surgical abortion in first trimester and for induction of labor in second and third trimesters. Misoprostol may also prevent postpartum hemorrhage when parenteral uterotonics are not available. The use of misoprostol in pregnant women has remained unapproved by US-FDA although in April 2002 it announced a revision in the labeling acknowledging the widespread off label use of misoprostol by obstetricians for cervical ripening and induction of labor and removes the previous contraindication for its use in pregnant women for this purpose.
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