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2002 Selected Articles

Use of Misoprostol in Obstetric Practice

John Patrick O’Grady, MD; David E. Seubert, MD; Christian S. Pope, DO; Despina E. Hoffman, BA

Misoprostol (Cytotec) is a methylester of prostaglandin E₁, commonly administered for cervical ripening and labor induction. Misoprostol has been approved by the US Food and Drug Administration (FDA) for the prevention of gastric ulcers in users of nonsteroidal anti-inflammatory drugs, and has been marketed for this indication since 1988. Controversy surrounds this drug due to efforts of the manufacturer, GD Searle (a division of Pharmacia), to restrict its use during pregnancy and because of complications reported following its administration.

The debate over misoprostol stems from the recent, rapid expansion of the originally approved drug indications to include "off-label" obstetric applications such as cervical ripening, labor induction, and medical abortion. Contributing to the controversy are the possible maternal-fetal complications attributed to misoprostol and its use as an abortifacient in countries where elective pregnancy termination is illegal.

There are differing opinions concerning misoprostol administration during pregnancy. Some institutions have prohibited or curtailed its use, while others restrict the drug to a specific protocol. Misoprostol has many advantages in comparison with alternative therapies, including stability at room temperature, low incidence of side effects, low cost, rapid absorption (both orally and vaginally), and high potency. Given these favorable features and the ongoing controversy, this article reviews the potential obstetric applications for misoprostol and presents a critical evaluation of the precautions necessary for its safe use (Table 1).

FIRST TRIMESTER

Elective Abortion

Pregnancy termination in the first trimester can be performed either surgically (suction curettage) or medically by administrating an antimetabolite (methotrexate) or a progesterone antagonist (mifepristone/RU-486) combined with a uterotonic. As a potential uterotonic, misoprostol has been approved by the FDA for early medical termination of pregnancy in conjunction with mifepristone.

Mifepristone.–The original FDA-approved regimen for first-trimester termination employs mifepristone, 600 mg orally, followed 48 hours later by misoprostol, 400 µg orally (Table 2).^1-3 Success rates with this dosing schedule approach 97%, with success defined as the number of abortions not requiring surgical intervention.^1-3 Under the original protocol, the success rate decreased to 88% in pregnancies of 56 days or more.

Vaginal administration of misoprostol is more effective than oral administration.^4,5 In a study utilizing mifepristone, 600 mg, followed 48 hours later by vaginal misoprostol, 800 µg, the success rate for first-trimester abortion was 93%. This is in comparison to 78% when oral misoprostol was substituted in the same regimen. The vaginal route also resulted in fewer adverse side effects. Based on these and other data, new protocols for first trimester abortion have successfully reduced the mifepristone dose to 200 mg while retaining the 800-µg dose of vaginal misoprostol.^3,6 This protocol results in efficacy comparable to the originally approved FDA dosing schedule, reduces cost, and extends treatment without compromise in success for up to 63 days of gestation.^2,3,7

Methotrexate.–Methotrexate, 50 mg/m² intramuscularly (IM) or 25 or 50 mg orally, followed 3 to 7 days later with vaginal misoprostol, 800 µg, is an alternative to the use of mifepristone. This regimen results in complete abortion rates of 88% to 100% (Table 2).^8-12 The principal disadvantage of methotrexate in comparison to mifepristone/misoprostol is a more delayed course and a higher incidence of procedure failure.

Missed Abortion

In cases of delayed or missed abortion (embryonic demise/blighted ovum), treatment is either medical (uterotonic) or surgical (curettage). In embryonic demise, vaginal misoprostol, 800 µg (repeated in 24 hours if necessary), is nearly 90% effective in achieving uterine evacuation within 48 hours.^9,13,14 Another protocol recommends vaginal misoprostol, 200 µg every 4 hours, until abortion or a maximum of four doses. Current data do not permit a direct comparison of these techniques with traditional surgical methods. However, misoprostol has proved less successful than curettage for completing an inevitable or incomplete spontaneous abortion, and is not recommended for this specific indication.

SECOND TRIMESTER

Elective Abortion/Labor Induction

Surgical abortion by dilatation and evacuation is the most common method for midtrimester pregnancy termination. Medical termination is also possible and, for some patients, is preferable. The principal methods for medical termination include intrauterine hypertonic saline or urea, parenteral oxytocin, intra-amniotic or intramuscular 15-methyl-prostaglandin F_2a(PGF_2a/carboprost), vaginal prostaglandin E₂ (PGE₂/dinoprostone), or misoprostol (vaginal or orally).^9,15,16 Many midtrimester protocols combine these modalities in various ways.

Complications of midtrimester pregnancy termination are common, and may be severe or complex. Administration of antibiotics, transfusion of blood or blood products, or surgical completion are occasionally required. Such termination procedures should not be initiated by an inexperienced clinician.

The appropriate misoprostol dose for midtrimester termination has not been established, as the data for review are limited.^9,15-17 Two dosing schedules reported to be effective are intravaginal misoprostol, 200 to 600 µg every 12 hours, or 400 µg orally every 3 hours for a maximum of 5 doses. These regimens result in successful abortion rates of 71% to 100%.⁹ Initial treatment with mifepristone, 200 µg every 36 to 48 hours, prior to the administration of misoprostol, improves the success rate.³¹ Comparison of misoprostol to other medical techniques for midtrimester pregnancy termination is not possible due to limited data and the polypharmacy accompanying most midtrimester procedures.

Preoperative Cervical Ripening

Misoprostol can also be used for preoperative cervical ripening in surgical abortion in the first and second trimesters. In the first trimester, the recommended dosing is misoprostol, 800 µg orally or vaginally, 3 to 4 hours prior to the procedure. The optimum dose for second-trimester cervical preoperative preparation has not been established. The suggested dose is 400 µg administered vaginally, 3 to 4 hours prior to the procedure. This dosing regimen is an extrapolation from available data.

Misoprostol pretreatment before surgical pregnancy termination (dilatation and curettage/evacuation) is not without potential complications. In the second trimester, there is an approximate 5% incidence of bleeding when vaginal misoprostol is administered for this indication. Other possible side effects include cramping, partial abortion, or low-grade fever.

THIRD TRIMESTER

Labor Induction

A number of methods are available for induction of labor at or near term. Misoprostol has become popular for term and near-term cervical ripening as a prelude to labor induction with oxytocin. Current data do not permit a full comparison of the various methods available for cervical ripening (Table 3).

The recommended starting dose for cervical ripening and labor induction is misoprostol, 25 µg orally or vaginally, administered no more frequently than every 4 to 6 hours; higher doses are associated with an increased risk of uterine tachysystole.^18-20 Oral administration is recommended in patients with preterm rupture of the membranes. There are insufficient published data to permit the evaluation of misoprostol use in multiple gestation, and clinicians should proceed with caution in such applications.

Fetal Demise.–In patients with fetal demise, the regimen is misoprostol, 200 to 400 µg vaginally, every 12 hours to a maximum of 1,200 µg in the first trimester, and misoprostol, 100 to 200 µg vaginally, every 12 hours for two doses in the second trimester. With this protocol, success rates approach 100%.^9,20 Alternative therapies include oxytocin alone, or oxytocin in combination with other prostaglandins mechanical methods of cervical dilatation (eg, Foley bulb or laminaria) or dilatation and evacuation. Despite favorable data, the case numbers in reported studies are limited. Clinicians should use prudence in proceeding with misoprostol administration in late-pregnancy fetal demise, as the best dose and schedule for treatment remain to be determined. Misoprostol should not be administered to women with a history of uterine surgery.

Prior Cesarean Delivery/Hysterotomy.–The routine use of misoprostol for cervical ripening and labor induction in women with a uterine scar is contraindicated. In parturients with a scarred uterus, the incidence of uterine rupture is greater following labor induction with misoprostol (5.6%) compared with women undergoing a trial of labor without misoprostol (0.2%).^9,21,22 It is uncertain whether misoprostol-induced uterine hyperstimulation is the culprit, or whether the problem is simply the use of any potent uterotonic in a patient with a scarred uterus when the cervix is unfavorable. In the third trimester, it is essential to wait for 4 hours or longer after the last misoprostol dose before administering oxytocin to reduce the risk of tachysystole.

POSTPARTUM USE

Active management of the third stage of childbirth with uterotonics limits blood loss and reduces the risk of uterine atony/postpartum hemorrhage (PPH), a major cause of maternal morbidity and mortality.²³ Because of its potent uterotonic effects, misoprostol has been studied for the prevention of PPH.^9,24,25 In a recent prospective study, misoprostol, 600 µg orally, immediately after cord clamping, limited the estimated blood loss to less than 500 mL in 94% of deliveries.²⁵ No cases in the study cohort had estimated blood losses of more than 1,000 mL. Prophylactic misoprostol treatment after delivery may prove as effective as oxytocin or ergometrine in reducing the risk of PPH, albeit at the cost of increased side effects.⁹ Oral misoprostol could prove to be the method of choice for PPH prophylaxis in parturients who lack established intravenous (IV) access. Additional information is required, and the effectiveness of oral misoprostol for this application remains under study.²⁶ The authors are currently conducting a randomized, prospective, double-blind, double-dummy dose study comparing oral misoprostol (200, 400, and 600 µg) with standard IV oxytocin.

Misoprostol also has a role in the treatment of acute PPH as a secondary agent in cases unresponsive to standard uterotonic therapy (eg, oxytocin, ergometrine, and 15 methyl-PGF_2a).²⁷ Currently, limited data and clinical experience support this application, but additional dosing/efficacy studies are needed. When treating PPH, misoprostol, 1,000 µg, is administered rectally. If control is achieved, initial therapy is followed by 400 to 600 µg orally every 3 to 4 hours for four doses in patients capable of oral intake. Rapid insertion of the required rectal dose is easily performed using one of the disposable plastic tubes equipped with a plunger that are supplied in packages of vaginal gel or cream.²⁷ The tube is loaded with the appropriate number of tablets, inserted rectally, and the plunger depressed to administer the dose. Onset of action occurs within minutes.

OTHER POTENTIAL USES

Several novel uses for misoprostol are under study. A local outpatient clinic service uses 400 µg of buccal misoprostol (200 µg/cheek) for cervical ripening 1 hour prior to midtrimester dilatation and evacuation. Minimal complications and high efficacy are claimed for this treatment. We await published data. Also, the authors have limited experience with substituting misoprostol, 100 to 300 µg orally, every 4 to 6 hours for four doses, for oral methylergonovine maleate (Methergine) in situations where a uterotonic is required but methylergonovine is either contraindicated or not desired. Initial results have been favorable. However, investigation of the appropriate dosing schedule and critical evaluation of the risks and benefits of this treatment versus standard therapy is yet to be performed.

SIDE EFFECTS

The most frequent side effects of misoprostol include nausea, vomiting, diarrhea, low-grade fever, and shivering.⁹ Dose-dependent uterine hypercontractility/hyperstimulation is an additional concern. A toxic dose has not been established. Cumulative doses of up to 2,200 µg every 12 hours have been administered without serious side effects. Unlike PGE₂ and PGF_2a, misoprostol does not cause bronchospasm and thus poses no theoretical risk in asthmatics.²⁸

In third-trimester cervical ripening/labor induction, uterine hyperstimulation/tachysystole depends on both the dose and the interval before oxytocin administration. In the largest available clinical series, the incidence of hyperstimulation was heightened, but clinical effects on the fetus were inconsequential, and there was no significant increase in cesarean deliveries.⁹ However, uterine tachysystole leads to physician and patient anxiety, and often to tocolytic therapy. If the fetal heart rate changes, parturients may be transported to the operating room, try a shift in position, receive oxygen, or undergo other treatments. Thus, the importance of this complication should not be underestimated. Additional dose/dosing schedule studies, strict timing of additive therapies (eg, oxytocin), use of lower starting doses, and close monitoring of uterine activity are required to reduce the risk of hyperstimulation and avoid potential adverse effects. Practitioners should adhere to their institutional protocols, especially for the time interval to oxytocin administration.

If misoprostol is administered in the first trimester and the pregnancy is not terminated, fetal anomalies may occur.⁹ It is theorized that misoprostol induces intense uterine contractions, leading to hypoperfusion and ultimately to vascular disruption. Associated malformations include cranial-nerve abnormalities (V, VI, VIII), arthrogryposis, terminal transverse limb defects, hydrocephalus, bladder exstrophy, holoprosencephaly, and the Möbius syndrome. The strength of this association remains unclear, and the absolute risk of anomaly is probably low.⁹ Nonetheless, in cases involving unsuccessful pregnancy termination with misoprostol, it is prudent to consider these gestations at risk for abnormality and counsel the patient/family accordingly.

The "off-label" use of misoprostol for indications not approved by the FDA is a concern to many clinicians. On occasion, as with misoprostol and the more familiar drug terbutaline, novel or off-label uses of a drug may actually eclipse the original package insert indications in popularity or clinical importance. In general, off-label prescribing is not considered experimental if it is rational and supported by a substantial body of scientific data, including evidence of widespread use. These qualifications have been met for misoprostol.^29,30 Due to the controversies concerning misoprostol, and given the possible complications inherent in the induction of labor, the authors require a specific, signed informed consent from the parturient when this drug is administered in a viable pregnancy. This is documented by a specific consent form and notation in the medical record (Figures 1 and 2).

CONCLUSION

The popularity of misoprostol has provoked a strong reaction. Misoprostol has been championed by some as a safe and inexpensive therapy for obstetric practice, while others have criticized its use in terms of unacceptable risk and inadequate testing. Following the rapid acceptance of misoprostol in obstetric practice, GD Searle took the unusual step of attempting to interdict obstetric use of the drug. This action was puzzling to many as data on safety and efficacy were not lacking.

Misoprostol is a potent and inexpensive uterotonic that can be administered by oral, vaginal, rectal, and buccal routes. The authors’ review of the literature provides support for its safe and effective use by protocol for first-trimester medical abortion as an adjunct with either mifepristone or methotrexate, and in third-trimester cervical ripening/labor induction. There is also an important potential use for this agent in both the prophylaxis and management of postpartum uterine atony/hemorrhage. Other possible uses are under study.

In terms of third-trimester use, misoprostol is less likely to require adjuvant uterotonics to supplement labor than other available agents/techniques, and has comparable neonatal outcomes. It must be emphasized that intervals from initiation of cervical ripening/labor induction to delivery are shorter with misoprostol- versus oxytocin-treated pregnancies. Use of this medication could prove cost-effective for labor induction, as inpatient hospital time is decreased and there is the potential to avoid the costs commonly incurred with oxytocin administration (eg, tubing, infusion pump, venipuncture, IV solutions).

Based on the available data and clinical experience, the authors contend that the cautious and restricted use of misoprostol is warranted given the strong and consistent evidence for its safety and efficacy. However, misoprostol is a potent drug that must be used prudently. This is especially true in clinical settings where reliable research data is limited and/or the drug is used in complex protocols with other uterotonics. The authors recommend establishing institution-specific practice guidelines and protocols to guide dosing and dose scheduling and careful chart documentation whenever misoprostol is administered. In summary, the authors are cautiously optimistic regarding the use of this potent uterotonic in selected obstetric settings and under conservative guidelines.

John Patrick O’Grady, MD, is a professor; David E. Seubert, MD, is an assistant professor; Christian S. Pope, DO, is a resident physician; and Despina E. Hoffman, BA, is a research assistant. All are members of the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology at Baystate Medical Center in Springfield, Mass, The Western Campus of Tufts University School of Medicine.

REFERENCES

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