Prostaglandins for first-trimester termination

Best Practice & Research Clinical Obstetrics & Gynaecology Vol. 17, No. 5, pp. 745 –763, 2003 doi:10.1016/S1521-6934(03)00070-1, www.elsevier.com/locate/jnlabr/ybeog

5 Prostaglandins for first-trimester termination Karen R. Meckstroth*

MD, MPH

Assistant Clinical Professor

Philip D. Darney

MD, MSc

Professor and Chief Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco General Hospital, Ward 6D, 1001 Potrero Ave., San Francisco, CA 94110, USA

Since the 1980s, when mifepristone combined with a prostaglandin was found to be safe and effective for early abortion, many studies have refined the regimens and investigated alternatives such as methotrexate plus misoprostol, and misoprostol alone. Evidence now demonstrates that more than 200 mg of mifepristone provides no additional benefit, that vaginal misoprostol is superior to oral, especially between 7 and 9 weeks’ gestation, and that misoprostol may be safely self-administered at home. Buccal and sublingual routes of administration of misoprostol also are promising. Absolute contraindications to medical abortion arise infrequently. Gastrointestinal and other side-effects occur in about one-third of women, primarily after administration of the prostaglandin. Careful assessment before and after medical abortion is essential and can be accomplished in various ways, depending on the skills of the clinician. Key words: abortion, induced; pregnancy trimester, first; abortifacient agents; prostaglandins; misoprostol; mifepristone.

Prostaglandins were known to terminate early pregnancy by the 1960s. Studies in the 1970s found that prostaglandins (PG) such as PGE2 and PGF2a caused early abortion but led to nausea, vomiting, diarrhoea, fever and pain severe enough to require treatment.1 In the 1980s, the development of the antiprogestin mifepristone led to extensive studies of medical abortion using mifepristone combined with various prostaglandins. The E-series prostaglandins, principally gemeprost and misoprostol, have been used most widely in combination with mifepristone because they stimulate uterine smooth muscle more than gut or vascular muscle, which are stimulated more by the F-series prostaglandins.2 When it became clear that mifepristone and gemeprost or misoprostol was efficacious and safe for early medical abortion to 8 or 9 weeks’ gestation, researchers to whom mifepristone was not available investigated alternatives, such as methotrexate combined with misoprostol, and misoprostol alone. Misoprostol is now the prostaglandin most commonly combined with mifepristone because it is inexpensive, heat-stable and easy to administer. It is licensed for oral use with * Corresponding author. Tel.: þ1-415-206-8358; Fax: þ1-415-206-3112. E-mail address: [email protected] (K. R. Meckstroth). 1521-6934/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.

746 K. R. Meckstroth and P. D. Darney

mifepristone up to 9 weeks’ gestation in many countries, although alternative routes of administration and a variety of evidenced-based protocols are commonly employed. It is estimated that 50 million voluntary abortions occur annually worldwide.3 In the USA over half of abortions are performed by 8 weeks’ gestation, and 87% of abortions are performed in the first 12 weeks.4 In other developed countries where early abortion is readily available, the proportion of pregnancies terminated in the first trimester is even greater. Medical abortion with prostaglandins offers an alternative to surgical abortion in countries where safe surgical abortion is available, and gradually is becoming an option for safe abortion where access to surgical abortion is restricted.

WORLD EXPERIENCE WITH MEDICAL ABORTION Mifepristone was first developed in 1980 in France, where it has been licensed since 1988 for use with a prostaglandin. It is now produced or licensed in many countries. France, China, the United States and most European countries have approved its use until 7 weeks, while the UK and Sweden approved use to 9 weeks gestation. The proportion of eligible women who choose medical over surgical abortion in countries where both are available varies. In France, Scotland and Sweden, 56, 51 and 61% of women, respectively elect medical over surgical abortion.5 In China, medical abortion is more common in cities, ranging from 30 to 70% of early abortions, and is rare at the township level.6 It is difficult to estimate the proportion of women who choose medical abortion in the USA because information about the use of mifepristone is still limited. In the first 6 months after mifepristone became available, about half of the abortion clinics offered medical abortion.7 In countries where abortion is restricted, women use misoprostol covertly to cause bleeding and abortion. Most evidence regarding the clandestine use of misoprostol originates from Brazil, where misoprostol has been more tightly regulated since 1991.8 Most likely, the irregular dosing and lack of follow-up that occurs with unsupervized use of misoprostol leads to decreased success, but women are able to avoid dangerous clandestine abortions. In some countries where abortion is illegal, safe uterine evacuation is available to pregnant women with incomplete abortions or uterine bleeding. Even in countries where safe abortion is available, women use misoprostol to induce abortion. For example, 5% of Latina women in New York City obstetrics and gynaecology clinics reported self-administration of misoprostol—higher than the proportion reported in a large Brazilian prenatal care population.9

CLINICAL REGIMENS Misoprostol alone Early studies of misoprostol used alone demonstrated rates of successful abortion of only 40 – 60%.10 – 12 Subsequently, Carbonell et al demonstrated improved success when tablets were moistened and placed vaginally. Up to three doses of 800 mg of misoprostol, placed vaginally after moistening achieved success rates over 90% in gestations up to 9 weeks.13,14 In further dosing studies, Carbonell et al found equal success and higher side-effects with 1000 mg, but much lower success (64%) with 600 mg.15,16 Initially, Carbonell’s studies involved rather elaborate protocols with douching prior to tablet insertion, and regimens of repeat administration. Jain et al

Prostaglandins for first-trimester termination 747

achieved success rates of 88 –94% up to 8 weeks’ gestation with simplified protocols using up to three doses of 800 mg of moistened, vaginal misoprostol.17 – 20 Although less complex than Carbonell’s, these protocols still required multiple sonographic evaluations and visits to the clinic. Two of these trials compared 800 mg moistened vaginal misoprostol alone to a combination of mifepristone and misoprostol to 8 weeks’ gestation. The first study compared women who received misoprostol alone to women who had received 600 mg mifepristone and 400 mg oral misoprostol in a previous study at the same clinic as part of a multi-centre trial in USA. Successful abortion occurred in 88% with misoprostol alone and in 94% with the combination.20 A subsequent randomized controlled trial compared misoprostol alone to 200 mg mifepristone combined with 800 mg vaginal misoprostol, and found a success rate for the single drug of 88, versus 95.7% for the combination.18 Time to complete abortion was slower, and additional doses of misoprostol were required more frequently with misoprostol alone. Although gastrointestinal and other misoprostol side-effects were similar in these trials, moistening tablets prior to vaginal administration has been shown to lead to increased side-effects.21 Grading the evidence and recommendations for use of misoprostol alone is complex. According to US Preventative Task Force grading, level I evidence confirms that misoprostol alone is less effective than mifepristone plus misoprostol, suggesting a D-level recommendation against the use of this protocol when mifepristone is available. Although efficacy is lower, level I evidence supports the safety of medical abortion with one to three doses of 800 mg moistened vaginal misoprostol alone. Because mifepristone is unavailable or prohibitively expensive in many countries, the lower efficacy of misoprostol alone may be considered acceptable. When misoprostol alone is employed by women without the guidance of a knowledgeable clinician, success rates may be lower and complications rates higher. Misoprostol is available in over 70 countries, is inexpensive and requires no refrigeration. For these reasons, an effective and simple regimen for medical abortion with misoprostol could benefit women who do not have access to other safe methods of abortion. Methotrexate combined with misoprostol Before mifepristone was approved in USA in September, 2000, investigators evaluated the alternative of methotrexate in combination with vaginal misoprostol. An antimetabolite similar to methotrexate was shown to cause abortions as early as 195022, and in 1993 Creinin and Darney evaluated low-dose methotrexate in combination with oral or vaginal misoprostol.23 Various doses of oral and intramuscular methotrexate followed 3– 7 days later by vaginal misoprostol, most commonly at the dose of 800 mg, were subsequently evaluated. Success rates ranged from 88 to 97% when the investigators followed patients for 30 – 45 days after the administration of methotrexate. Although most studies evaluated women with gestations up to 8 weeks, several studies found this combination to be safe and effective up to 9 weeks’ gestation.24 – 27 The first meta-analysis of medical abortion regimens found no difference in overall efficacy between methotrexate regimens and mifepristone regimens, to 56 days’ gestation.28 The primary difference was that up to 20 –30% of women using methotrexate waited up to 5 weeks for a successful abortion.29 A recent randomized controlled trial of 1042 women compared common regimens of mifepristone and methotrexate (mifepristone 600 mg orally plus misoprostol 400 mg orally 48 hours later, versus methotrexate 50 mg/m2 intramuscularly and misoprostol 800 mg vaginally 48 hours later). They concluded that, although the overall success

748 K. R. Meckstroth and P. D. Darney

rates, side-effects and complications were similar, mifepristone led to faster completion of abortion and was more acceptable to women.30 Methotrexate was primarily used in USA prior to the availability of mifepristone, but mifepristone is now preferred. The only trial that has compared methotrexate and misoprostol to misoprostol alone found the methotrexate combination to be superior to 800 mg dry vaginal misoprostol alone10, but the low rate of success with misoprostol alone (47%) was inconsistent with success rates (88 –94%) in trials in which misoprostol was moistened. Mifepristone combined with a prostaglandin The most widely studied regimen for early medical abortion is mifepristone in combination with misoprostol or gemeprost. Mifepristone is a synthetic steroid and progesterone antagonist that binds to progesterone receptors and blocks the action of endogenous progesterone. During pregnancy, progesterone maintains the uterus in a quiescent state by inducing hyperpolarization of the cell membrane. When the action of progesterone is blocked from the pregnant uterus, the electrical excitability of the myometrium increases, and gap junctions between the myometrial cells permit coordinated uterine contractions. Mifepristone also induces cervical ripening, probably due to an increase in endogenous prostaglandins31,32, although some studies have not been able to demonstrate an increase.33,34 The resulting cervical ripening, uterine contractions and decidual necrosis lead to abortion. Mifepristone alone achieves complete abortion in only about 60– 80% of women, even with high doses and up to 6 weeks of follow-up. The percentage of continuing pregnancies after mifepristone alone ranges from 7 to 40%.35 – 38 Mifepristone combined with misoprostol or gemeprost leads to a successful abortion rate of 95% or higher in women with pregnancies up to 9 weeks’ gestation. After four serious cardiovascular complications (one myocardial infarction and three cases of severe hypotension) were reported with the use of the parenteral PGE2 sulprostone, use of this prostaglandin for medical abortion was abandoned.39 Gemeprost, a PGE1 analogue manufactured as a vaginal suppository, was widely studied in France and the UK in combination with mifepristone.39,40 Misoprostol is currently the prostaglandin most commonly combined with mifepristone. In ‘standard’ regimens approved by national regulatory agencies, mifepristone 600 mg orally is followed approximately 48 hours later by 400 mg oral misoprostol given in the clinic. Alternative evidenced-based regimens can provide better efficacy, safety and acceptability.

FACTORS INFLUENCING EFFICACY Medical abortion is typically considered a success when a woman passes the pregnancy after medications and does not require surgical uterine evacuation for continuing pregnancy, incomplete abortion, prolonged or heavy bleeding, or patient request. In contrast, surgical abortion is usually considered a success if the pregnancy does not continue. Re-aspirations for the conditions listed above are not considered failures but complications. Given these definitions, medical abortion has a lower overall success rate than does surgical abortion. With improved dosing regimens at early gestation, however, success and continuing pregnancy rates of medical and surgical abortion are very similar.41,42 In addition to medication factors, several patient and provider characteristics may affect efficacy rates of medical abortion.

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Gestational duration is an important predictor of outcome. The most recent metaanalysis of medical abortion found that, as gestation advanced from 7 to 9 weeks, success rates of mifepristone plus misoprostol, and methotrexate plus misoprostol, declined from 95 to 84%. However, the analysis did not observe this decline for mifepristone plus other prostaglandins.28 Nor do most studies of mifepristone plus vaginal misoprostol show a decline in efficacy as gestation approaches 9 weeks. Large studies of 200 mg mifepristone followed by 800 mg vaginal misoprostol achieve success rates over 95%, with failure due to ongoing pregnancy in only about 1% of women.43 – 47 Several large trials have reported that parous women have an increased failure rate compared to nulliparous women.41,48 – 50 Some studies also have noted decreased success in women with prior elective abortions compared to women without prior abortions.48,51 The reasons for these trends are unknown. One analysis found decreased success using mifepristone plus a prostaglandin with increasing beta human chorionic gonadotropin (hCG) value and body mass index.52 Experience with medical abortion improves counselling and familiarizes clinicians with the course of medical abortion. When both patient and clinician are familiar with normal variations in bleeding, pain and other side-effects, intervention is less frequent. This decline in surgical intervention with experience has been documented in studies of methotrexate53, and is suggested by the lower success rates found in the initial US multi-centre trial, compared to countries where providers were experienced.51,54 EVIDENCE FOR REVISED PROTOCOLS Lower dose of mifepristone Pharmacological studies find that serum transport proteins are saturated with doses of mifepristone of 100 mg or more55, so it is not surprising that randomized studies find no differences in medical abortion success when 200, 400 and 600 mg doses are compared.56,57 A mifepristone dose of 50 mg was, however, less effective than 200 mg in a WHO trial.58 A small trial of 100 mg mifepristone led to high efficacy when combined with vaginal misoprostol, but lower efficacy with oral misoprostol.59 Misoprostol versus gemeprost after mifepristone Baird et al evaluated mifepristone combined with vaginal gemeprost versus oral misoprostol. They found no difference in efficacy to 9 weeks’ gestation, although more continuing pregnancies after 7 weeks’ gestation occurred in the group who received oral misoprostol.60 A subsequent trial of nearly 1000 women compared 200 mg mifepristone combined with 1 mg vaginal gemeprost, versus 800 mg vaginal misoprostol, and found a small but significant increase in success with the vaginal misoprostol regimen, 96.2 versus 98.7%, respectively.61 Both misoprostol and gemeprost are appropriate for use with mifepristone. Gestational duration limits Medical abortion has been most extensively studied to 7 weeks’ gestation. Multiple studies have, however, established the safety, efficacy and acceptability of outpatient medical abortion to 9 weeks’ gestation with mifepristone plus vaginal misoprostol or gemeprost.43,44,62 Mifepristone plus misoprostol is less effective between 7 and 9

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weeks, however, when the misoprostol is administered orally.21,51,54 Side-effects such as vomiting and diarrhoea appear to be increased as gestational duration increases.44 There are few studies of medical abortion between 9 and 13 weeks’ gestation, when vacuum aspiration is the accepted method of pregnancy termination. Ashok et al carried out a partially randomized controlled trial of medical abortion between 10 and 13 weeks with mifepristone and misoprostol. Two days after receiving 200 mg of mifepristone, women were admitted to the hospital for administration of 800 mg of vaginal misoprostol, followed by 400 mg misoprostol every 3 hours up to three doses total. The median induction interval with misoprostol was 5 hours, with a range of 2 – 28 hours. Overall, 94.6% of medical abortions and 97.9% of surgical abortions were successful and did not require a further procedure.63 Carbonell et al conducted three trials of misoprostol alone for late first-trimester abortion with success rates ranging from 84 to 87%.64 – 66 Alternative routes of administration of misoprostol Misoprostol tablets are manufactured for oral administration. Many studies have demonstrated the efficacy and acceptability of administering these tablets vaginally for early abortion. Several randomized trials have found that, compared with oral misoprostol, vaginal administration of misoprostol is more effective, faster, and has a lower rate of ongoing pregnancy, and fewer gastrointestinal side-effects, especially between 7 and 9 weeks’ gestation.46,62,67 Vaginal tablets frequently dissolve incompletely, and pharmacokinetic studies have confirmed wide variability in serum levels with vaginal administration.68,69 Studies of uterine contractility, however, reveal that the absorption and serum levels of misoprostol do not fully explain its action on the pregnant uterus. Gemzell Danielsson et al demonstrated that regular uterine contractions are more reliably produced by vaginal misoprostol than oral misoprostol, even with similar serum levels.68 Observational studies of misoprostol alone suggest that wetting the tablets improves success. The three randomized trials of moistening misoprostol, when used alone or with methotrexate, did not demonstrate significantly improved success with moistening the tablets.21,70,71 Increased side-effects observed in these trials suggest that moistening does increase absorption, however. No trials have investigated moistening misoprostol tablets when used with mifepristone, which is highly efficacious when tablets are used dry. Other issues with vaginal use include the inconvenience of vaginal placement and women’s preference for oral administration. Given these concerns, sublingual and buccal administration have been investigated and are promising alternatives. As with vaginal administration, the medication is absorbed directly and avoids the gastrointestinal system. Trials of buccal misoprostol for early abortion are yet unpublished, but it was similar to vaginal administration for term labour induction.72 Small trials of sublingual misoprostol alone have found similar success rates to vaginal misoprostol for early elective and missed abortion73 – 75, and one case series of 100 women who received 200 mg mifepristone, followed 48 hours later by 800 mg sublingual misoprostol, achieved a 94% success rate.76 Dose and timing of misoprostol Because side-effects increase with the dose of misoprostol, the lowest effective dose for each route of administration is ideal. Unfortunately, comparative dose-finding studies of misoprostol, used alone or in combination, are few. A comparison of misoprostol, given vaginally 1, 2, or 3 days after mifepristone, found no difference in

Prostaglandins for first-trimester termination 751

efficacy.77 Some protocols require multiple doses of misoprostol after mifepristone. A second oral misoprostol dose appears to lead to higher overall efficacy, and may mitigate the influence of gestational length on efficacy with oral misoprostol.28,48 The ideal interval between the doses is not clear, however. A week-long course of oral misoprostol (400 mg twice daily), was not beneficial in reducing blood loss or improving efficacy.78 Home administration of misoprostol Initially, protocols of medical abortion stated that women should be observed in the clinic for several hours after administration of misoprostol. The advantage for some women is the availability of immediate medical attention for side-effects or questions and, for some, the company of other women undergoing the same experience. Selfadministration of misoprostol at home has the advantage of avoiding an additional visit to the clinic and providing privacy, a familiar atmosphere and family support for the woman.79 Multiple studies of mifepristone plus misoprostol, and misoprostol alone have confirmed that home administration of oral or vaginal misoprostol is safe and acceptable to most women. Several of Schaff’s studies demonstrated high efficacy through 5645,77 or 6344 days’ gestation. Approximately 90% of subjects in these studies found home use of misoprostol acceptable, regardless of prior abortion experience, gestational age, or time between mifepristone and misoprostol. Assessment before medical abortion The assessment before medical abortion includes † † † †

ascertainment of the woman’s desire for termination of pregnancy; evaluation for absolute or relative contraindications; assessment of gestational duration; Rh status.

Pregnancy options counselling, physical examination, tests for sexually transmitted infections, haemoglobin level or other laboratory tests and contraception counselling may also be appropriate. Assessment of pregnancy and gestational age When providing medical abortion, accurate evaluation of early pregnancy is important to achieve highest efficacy and avoid complications. Ultrasound is commonly used in the USA for pregnancy dating before medical abortion, but it is not immediately available to many clinicians and it adds expense to the provision of medical abortion. However, it permits accurate determination of gestational duration, as well as diagnosis of ectopic pregnancy, uterine myomas and rare hydatidiform moles, which may affect the outcome and experience of medical abortion. In other countries, ultrasound is performed only when determination of pregnancy duration by uterine palpation is inconsistent with time since last menses, a protocol that has demonstrated high efficacy and safety when combined with careful follow-up. Experienced providers in France, for example, use ultrasound in about 30% of cases. Date of last menstrual period (LMP) alone does not appear to lead to accurate diagnosis of gestational age. A re-analysis of a Population Council multicentre trial

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demonstrated that in 40 – 60% of subjects, gestational length estimates were adjusted from the estimate by LMP after ultrasound evaluation.80 In women seeking abortion with methotrexate and misoprostol in the USA, gestational duration by LMP was confirmed for only 50– 60% of study participants.81 A recent study noted limitations with pelvic examinations as well. In this study, pelvic examination agreed with ultrasound (^ 2 weeks) in 92% of cases for faculty and 75% for resident physicians.82 This result suggests that less experienced clinicians may require ultrasound for accurate estimation of gestational duration. Human chorionic gonadotropin levels alone are not ideal for evaluation of gestational duration because they are highly variable in the first trimester, especially after 42 days.83 Cut-off values that exclude women over 7 weeks have only fair specificity and exclude many eligible women, while cut-off levels with high sensitivity for eligibility also include women with later gestations. One study found a beta-hCG cut-off of 71 160 mIU/ml to have a sensitivity of 95% and specificity of 62% for detecting gestations of less than 7 weeks, while a cut-off of 23 745 mIU/ml had a sensitivity of 96% and specificity of 91% for detecting gestations of less than 6 weeks.83 Anti-D immune globulin The incidence of isoimmunization with first-trimester abortion is unknown. Because fetal red blood cells have been identified in maternal blood in the first trimester, the 50 mg dose of anti-D immune globulin is recommended for Rh-negative women who undergo medical abortion.84 While it is unlikely that gestations of 4 or 5 weeks could produce isoimmunization, prophylaxis is recommended until evidence confirms that it is not warranted. Confirmation of complete abortion Because misoprostol and methotrexate are teratogens, it is essential to confirm termination of pregnancy after medical abortion. Confirmation may be accomplished in a number of ways, including ultrasound, visualization of products of conception, sensitive urine pregnancy tests, and serum hCG. In the USA, ultrasound has been used in all studies. In clinics where women are observed for several hours after the administration of misoprostol, collection of expelled tissue confirms completion of abortion. A decrease in serum beta-hCG may be used to demonstrate termination of pregnancy, with symptomatic follow-up for evidence of incomplete abortion. One trial of beta-hCG after methotrexate abortion found that if the beta-hCG level had not declined by a minimum of approximately 50% over 24 hours, the abortion was unlikely to be complete.85 Harper et al suggest that a follow-up visit to the clinic may be avoided with the use of home pregnancy tests combined with phone follow-up.86 This may delay the diagnosis of complete abortion for some women because urine hCG can remain positive for over a month after successful medical abortion.87 In a recent study of betahCG after mifepristone and misoprostol abortion, however, nearly all women had undetectable serum beta-hCG by 14 days.88 When an intrauterine pregnancy has not been confirmed by ultrasound before medical abortion, the follow-up evaluation also must exclude ectopic pregnancy. One study of very early pregnancies (before a gestational sac could be visualized with ultrasound) used a 50% drop in beta-hCG to confirm discontinuation of the pregnancy. In this study, women with a beta-hCG above 2000 IU/l were evaluated for ectopic pregnancy prior to mifepristone.89

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CONTRAINDICATIONS There are few absolute contraindications to medical abortion. Relative social and psychological precautions appear more frequently. Table 1 lists contraindications and the reasoning behind them. Women with a scarred uterus Women with a scarred uterus from a prior caesarean section or other surgery, have not been excluded from trials of early medical abortion, and studies evaluating that subgroup have found no increase in complications.92 There are no confirmed cases of uterine rupture in the first trimester. The earliest reported case with prostaglandin induction occurred at 18 weeks following mifepristone and misoprostol induction.93 There are no reported cases with short-term (less than 8 hours) prostaglandin use for cervical ripening in the second trimester, although there are rare reports of spontaneous uterine rupture in the second trimester of both scarred and unscarred uteruses.94

COMPLICATIONS AND SIDE-EFFECTS Serious complications with medical abortion are rare. With surgical abortion, adverse events, such as uterine perforation and anaesthesia complications, result from the need to instrument the uterus, which is avoided with successful medical abortion. Unlike surgical abortion95, prophylactic antibiotics are not usually employed to prevent infection after medical abortion. It is important to note that, where abortion is legal and available, complications of surgical abortion also are rare. A report of 170 000 firsttrimester surgical abortions performed by experienced providers in the USA noted an overall complication rate of nine events per 1000 procedures.96 Non-randomized comparisons of mifepristone plus a prostaglandin versus surgical abortion have been small, and have not detected differences in complication rates. Both evaluations of mifepristone plus misoprostol versus vacuum aspiration to 9 weeks’ gestation have found about a 4% higher rate of post-abortion surgical intervention after medical abortion.41,97 Compared to later in pregnancy, higher doses of prostaglandin are required to cause uterine activity in the first trimester. These higher doses are associated with more frequent gastrointestinal effects and thermoregulatory effects, such as fever or chills. The proportion of women who note various side-effects varies depending on how and when responses were recorded in studies. Many women experience nausea and vomiting in early pregnancy, so these side-effects may be present before administration of medical abortion medications. In such cases, prophylactic antiemetic medication may be appropriate. Although a small percentage of women experience nausea or vomiting after mifepristone, nausea, vomiting and diarrhoea most commonly occur after misoprostol. Usually these effects are limited to one or a few episodes, and resolve without medication. No studies have evaluated prophylactic treatment for nausea, vomiting or diarrhoea with mifepristone and misoprostol. One randomized trial of loperamide before use of misoprostol alone found decreased diarrhoea.17 Ranges for side-effects and complications of medical abortion are noted in Table 2.

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Table 1. Absolute and relative contraindications to early medical abortion. Contraindications † Known allergy to one of the medications

Reasoning/comments Allergy to mifepristone or prostaglandin is extremely rare

† Coagulopathy or concurrent anticoagulation

Increased risk of haemorrhage in an unsupervized setting

† Concurrent systemic corticosteroid use or adrenal failure

Mifepristone has antiglucocorticoid effects

† Suspected ectopic pregnancy

Neither mifepristone nor prostaglandins is effective treatment for ectopic pregnancy. Patient management protocols for treatment of ectopic pregnancy with methotrexate are often different from those of medical abortion

† IUD in place

Strong uterine contractions against an IUD is a theoretical risk; an IUD may be removed immediately before medical abortion

† Inherited porphyrias

Progesterone has been implicated in pathogenesis of acute attacks of porphyria, and studies in chick embryos suggest that mifepristone could increase attacks90

Relative contraindications † Unwilling to undergo a surgical abortion if required

Reasoning/comments Surgical abortion serves as back-up in emergency; continuing pregnancies are exposed to teratogens

† Large or symptomatic uterine fibroids

May impair uterine contraction and increase bleeding; may be appropriate in an inpatient setting

† Severe anaemia

Unsupervized bleeding puts patient at higher risk

† Poorly controlled bowel disease

Misoprostol and other prostaglandins increase bowel motility and may cause diarrhoea

† Uncontrolled seizures

May be inappropriate for outpatient abortion and self-care

† Significant cardiovascular or cerebrovascular disease

May be inappropriate for outpatient abortion; mifepristone, misoprostol, gemeprost and methotrexate have no known direct cardiovascular effects and no events have been reported

† Other significant systemic illness

May be inappropriate for outpatient abortion; most clinical trials have excluded women with severe medical conditions (continued on next page)

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Table 1. (continued) † Breastfeeding

No studies have addressed breastfeeding; both misoprostol and mifepristone are excreted in breast milk; mifepristone is undetectable after 11 days and misoprostol is cleared in less than 2 days69,91

Relative social and psychological contraindications † Anxious to have abortion over quickly † Cannot return for follow-up visits † No access to phone or transportation in case of emergency † Difficulty understanding instructions † Does not wish to take responsibility for own care at home

Uterine bleeding and haemorrhage Uterine bleeding is an expected effect of the medical abortion process. About 25% of women have bleeding after mifepristone, a proportion which is increased with longer

Table 2. Percentage of women experiencing side-effects and complications after mifepristone plus misoprostol for medical abortion. % of women

Reference

Side-effect Uterine bleeding Bleeding longer than 30 days Bleeding before misoprostol (after mifepristone) Abdominal pain requiring narcotic analgesia Nausea Vomiting Diarrhoea Chills or fever Headache Dizziness

95–100 9 21–47 29–73 20–65 10–44 3–29 7–44 27–32 12–38

51 45,98 45,51 44,51 44,51 44,51 44,51 44,51 44,51

Complication Haemorrhage requiring transfusion Endometritis

0.1–0.2 0.3–0.5

39,43,51 44,51

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duration between mifepristone and misoprostol.51,98 Bleeding may begin within a half hour after misoprostol administration or may be delayed. Heavy bleeding is expected with successful passage of the pregnancy. Of women who have successful abortions, expulsion occurs within 6 hours in about 68%, and within 24 hours in about 90%.28 Large trials found that bleeding lasts an average of 8– 17 days, with a range of 1 to over 60 days.39,51 Even with prolonged bleeding, clinically significant changes in haemoglobin rarely occur. Most trials report no transfusions, and those large trials in which subjects have received transfusions report an incidence of 0.1 – 0.2%39,51 Abdominal pain Analgesics are the most common additional medications prescribed with medical abortion medications. Women may use acetaminophen, a non-steroidal anti-inflammatory drug, or a narcotic. Two trials have investigated pre-medication before the onset of pain. One found no improvement in pain scores or incidence of severe pain with a methotrexate protocol.99 The other found decreased opiate use with pre-medication with acetaminophen, when misoprostol is used alone for abortion.17 Although part of the mechanism of action of mifepristone and prostaglandins may be to induce production of endogenous prostaglandins, there is no evidence that non-steroidal medications decrease the success rate of abortion. One randomized trial found no difference in efficacy if women using methotrexate plus misoprostol took non-steroidal medication.100 Among women in a large multi-centre trial in USA, which clinic the subject attended was the strongest predictor of narcotic medication use. Narcotic use was less prevalent in women with gestations 56 days or less, parous women, and Asian women.101,102 We recommend that women be prescribed an oral narcotic medication, so that it is available if necessary. Exposure to teratogens Mifepristone has no known teratogenic effects. Exposure to misoprostol in early pregnancy has been associated with multiple congenital defects. Vasoconstriction during uterine contractions leading to distal ischaemia is a primary proposed mechanism for the anomalies. The odds ratio of exposure to misoprostol in infants with Mobius sequence (congenital facial paralysis with or without limb defects) has been shown to be 29.7 (95% CI 11.6 – 76.0).103 The relative risk of malformations after exposure to misoprostol cannot be quantified because most information is derived from case reports and retrospective analyses from Brazil where misoprostol is used for self-induced, illegal abortion. On an epidemiological level, analysis of the Latin American Collaborative Study of Congenital Malformations, an ongoing database of infants with congenital anomalies, found no difference in exposure to misoprostol in over 4500 affected infants compared to unaffected infants.104

ACCEPTABILITY OF MEDICAL ABORTION Women in trials of medical abortion express a high degree of satisfaction with the method. In a large multicentre in USA, trial 91.2% of women said that they would choose the method again, and 95.7% would recommend it to a friend.105 A comparison

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of women who chose surgical or medical abortion found that women who underwent medical abortion were more satisfied, and more likely to choose the same procedure again in the future. Increased anxiety during surgical abortion and failure of medical abortion were associated with the preference for the alternative regimen in the future.106 Among women who had no preference for medical or surgical abortion and who agreed to be randomized, the acceptability for medical abortion was lower than surgical abortion.107

CERVICAL RIPENING BEFORE SURGICAL ABORTION Misoprostol also has been extensively investigated for cervical preparation prior to surgical pregnancy termination. The cervical softening and dilation reduces the need for mechanical dilators, and therefore the opportunity for uterine perforation. Dosefinding studies have determined that 400 mg of vaginal misoprostol, 3– 4 hours prior to the procedure, is optimal for achieving adequate dilation in over 95% of women before first-trimester surgical termination. When additional mechanical dilation is required following misoprostol, it is easier than when additional dilation is required after laminaria.108 No additional success is achieved with 600 or 800 mg, and women experience increased side-effects. Less time (2 hours) and lower doses (200 mg) are less likely to provide adequate dilation. Oral administration of 400 mg misoprostol for 3– 4 hours is less effective than vaginal.108 Oral misoprostol at a higher dose (600 mg) for longer duration (8– 12 hours) may achieve dilation similar to that with vaginal administration, but results are inconsistent.109,110 Buccal misoprostol has been evaluated for cervical ripening before second-trimester abortion and found to be effective.111,112

SUMMARY In the past decade, early pregnancy termination using prostaglandins in combination with mifepristone has become an option for many women around the world. Misoprostol is the most commonly used prostaglandin because, unlike gemeprost and other prostaglandins, it does not require refrigeration, is inexpensive and is widely available. Extensive research supports the safety, efficacy and acceptability of standard regimens of mifepristone plus misoprostol, as well as adaptations of these regimens to 9 weeks’ gestation. Many regulatory agencies and clinicians, however, choose to limit medical abortion to 7 or 8 weeks’ gestation owing to increased side-effects and failures with advancing gestational duration. It is now clear that more than 200 mg of mifepristone provides no additional benefit, that vaginal misoprostol is superior to oral administration between 7 and 9 weeks’ gestation, and that misoprostol may be safely self-administered at home. Buccal and sublingual misoprostol may have effects similar to those of vaginal administration, as well as improved tolerance for women and convenience for clinicians. Research on these alternative routes of administration is in progress. Side-effects, primarily gastrointestinal and thermoregulatory effects, occur in about a third of women, but are generally of short duration and are well tolerated without medication. Bleeding and abdominal pain are expected with medical pregnancy termination and are tolerated by women when they receive appropriate counselling

758 K. R. Meckstroth and P. D. Darney

Table 3. US Preventative Task Force recommendations. Strength of recommendation Rating A: good evidence to support Rating B: fair evidence to support Rating C: insufficient evidence to recommend Rating D: fair evidence against Rating E: good evidence against Quality of evidence Level I: evidence from one or more randomized controlled trials Level II-1: evidence from controlled trials, but no randomization Level II-2: Evidence from cohort or case– control studies Level II-3: evidence from multiple time or historic controls Level III: expert opinion based on clinical experience

and pain medication if needed. Absolute contraindications to medical abortion are rarely encountered, but careful evaluation prior to, and following, medical abortion is essential. Interactive counselling regarding the process, side-effects and efficacy of medical abortion facilitates identification of appropriate candidates for medical abortion versus women who may prefer, or who may be better served by, surgical abortion. Practice points † mifepristone þ vaginal misoprostol or gemeprost is safe, effective and acceptable to 9 weeks’ gestation. Mifepristone þ oral misoprostol is less effective after 7 weeks † gastrointestinal side-effects are lower with vaginal administration † 200 mg mifepristone is as effective as higher doses; 100 mg mifepristone may be effective with 800 mg vaginal misoprostol, but 50 mg mifepristone leads to lower success rates † similar success rates are obtained when 800 mg vaginal misoprostol is administered 1, 2 or 3 days after mifepristone † a second dose of misoprostol, if needed after mifepristone, increases overall efficacy † medical abortion may have slightly decreased success when the woman is parous, obese, has a higher beta-hCG or has had prior elective abortions. Success increases when the clinician is experienced with medical abortion † level I evidence supports an A-level recommendation (see Table 3) for 200 mg oral mifepristone followed 1, 2 or 3 days later by 800 mg of vaginal misoprostol, self-administered at home, with follow-up 4– 14 days later † level I evidence supports an A-level recommendation for methotrexate (50 mg/m2 intramuscularly or orally) plus misoprostol 800 mg vaginally 3 – 7 days later. However, the longer time to abortion and decreased acceptability suggests that mifepristone is preferable, when available † two to three doses of 800 mg of moistened vaginal misoprostol alone is approximately 8% less effective than the combination of mifepristone plus misoprostol

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Research agenda † optimal dose and timing of misoprostol after mifepristone † efficacy of sublingual and buccal misoprostol alone and after mifepristone † simplified protocols for misoprostol alone for use where mifepristone is not available † alternatives to ultrasound for initial evaluation and confirmation of complete abortion † the risk of anti-D rhesus iso-immunization in very early pregnancy † best counselling strategies for medical abortion

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