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Obstetrics & Gynecology 2001;97:11-16
© 2001 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Early Medical Abortion With Methotrexate and Misoprostol

LYNN BORGATTA, MD, MPH, MICHAEL S. BURNHILL, MD, DMSC{dagger}, JUDITH TYSON, MD, KATHRYN K. LEONHARDT, MD, MPH, RICHARD U. HAUSKNECHT, MD and SUE HASKELL, DO

From Planned Parenthood Federation of America, Inc., New York, New York; Planned Parenthood of Northern New England, Inc., Williston, Vermont; Planned Parenthood of Wisconsin, Inc., Milwaukee, Wisconsin; Planned Parenthood of New York City, Inc., New York, New York; and Planned Parenthood of Greater Iowa, Inc., Des Moines, Iowa.

Address reprint requests to: Medical Division Planned Parenthood Federation of America, Inc. 810 7th Avenue New York, NY 10019


   Abstract
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Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To evaluate the introduction of an early medical abortion program with methotrexate and misoprostol, using a standardized protocol.

Methods: A total of 1973 women at 34 Planned Parenthood sites participated in a case series of early medical abortion. Ultrasound was used to confirm gestational age of less than 49 days from the first day of the last menstrual period. Women were given intramuscular methotrexate 50 mg/m2 of body surface area on day 1, and then they inserted misoprostol 800 µg vaginally at home on day 5, 6, or 7. Women were advised to have a suction curettage if the pregnancy appeared viable 2 weeks after methotrexate or if any gestational sac persisted 4 weeks after methotrexate. Outcomes were complete medical abortion and suction curettage.

Results: Sixteen hundred fifty-nine women (84.1%) had a complete medical abortion, and 257 (13.0%) had suction curettage. The most common reason for curettage was patient option (8.9%). At 2 weeks after methotrexate use, 1.4% of women had curettage because of a viable pregnancy; at 4 weeks, 1.6% of women had curettage because of a persistent but nonviable pregnancy. One percent of women had curettage because of physician recommendation, most commonly for bleeding. Suction curettage rates decreased with site experience (P < .006) and were lower at early gestational ages (P < .004) and in nulliparous women (P < .004).

Conclusion: Medical abortion with methotrexate and misoprostol is safe and effective and can be offered in a community setting.

Early medical abortion provides an alternative to surgical abortion. Methotrexate combined with misoprostol is currently the early medical abortion technique used most widely in the United States and Canada. The combination of intramuscular methotrexate and misoprostol has been shown to be safe and effective in several studies.1–4

Worldwide, mifepristone has been the most widely used medical abortion agent, starting with approval in France in 1988, followed by approval in the United Kingdom, China, Russia, Austria, Belgium, Denmark, Finland, Germany, Greece, Israel, Spain, the Netherlands, and Switzerland.5 However, mifepristone is not currently available in North America except through several research centers. In contrast, methotrexate is readily available because it is approved for other uses in the United States and Canada; it is also inexpensive. Efficacy of methotrexate and misoprostol and mifepristone and misoprostol at gestations of 49 days or less is similar, ranging from 83–96% for methotrexate to 92–97% for mifepristone.1–7 Given the availability and efficacy of methotrexate, Planned Parenthood Federation of America, Inc. investigated the feasibility of medical abortion services.

Planned Parenthood affiliates provide approximately 12% of all abortions in the United States and serve a population that is socially, economically, and ethnically diverse. Clinician background, training, and prior research experience at individual sites also vary. We designed a prospective case series of early medical abortion using methotrexate and misoprostol.


   Materials and Methods
Top
Abstract
 Materials and Methods
Results
 Discussion
 References
 
Planned Parenthood sites that already provide surgical abortion services were invited to participate in a study of medical abortion using methotrexate and misoprostol. The invited sites were required to have vaginal ultrasound capability and at least two physicians as investigators to provide clinical care as needed. Women under 18 years old required parental consent to enroll. Independent Review Consultants, Inc., an independent institutional review board, approved the study.

Women were eligible if they were at no more than the equivalent of day 49 of their menstrual cycle, confirmed by vaginal ultrasound examination on the day of enrollment. Our model for dating was similar to that of Weibe,8 which was adapted from Goldstein and Wolfson9 and Rossavik et al10: gestational age (days) = embryonic pole length (mm) + 42. In the absence of an embryonic pole, the model was gestational age (days) = mean gestational sac diameter (mm) + 30.

Assessment of gestational age was based on menstrual history, unless the ultrasound examination differed by at least 3 days, in which case the ultrasound estimate was used. If a gestational sac was not visible, a serum ß-hCG level was done; if it was less than 2000 mIU/mL, the woman could enroll. If the ß-hCG level was over 2000 mIU/mL, the woman was asymptomatic, and the site was approved to manage ectopic pregnancies, she could enroll.

We excluded women with a hematocrit less than 30%, history of severe renal or hepatic disease, an immune deficiency such as AIDS, cardiac disease (American Heart Association class 3 or worse), known coagulopathy, or who were taking anticoagulants. We also excluded women who were unwilling to have a suction curettage at the study site if it were needed.

Sites charged the same fee for methotrexate and misoprostol abortion as for a surgical abortion; the fee included suction curettage if needed.

The dose of methotrexate was 50 mg/m2 of body surface area given intramuscularly on day 1. Rh-negative women received minidose Rh immune globulin on day 1. Eight 200-µg misoprostol tablets were dispensed to each patient. Women were instructed to place four tablets (800 µg) as high as possible in the vagina on day 5, 6, or 7, according to scheduling preferences. After 24–48 hours, the woman inserted the second dose of four misoprostol tablets unless she believed that the abortion was complete according to the instructions she received at the site.

A return visit was scheduled by day 14–16. If the visit on or before day 14 showed a complete abortion, another visit was not required. If an ultrasound on day 14 showed a nonviable pregnancy, the woman was instructed to return by day 27–29. Women were advised to have a suction curettage if ultrasound showed a viable pregnancy on day 14–16 or if ultrasound showed any gestational sac on day 27–29. After day 14, if the pregnancy was nonviable, a third dose of 800 µg of misoprostol could be prescribed.

Women were asked to rate the degree of bleeding, cramping, and adverse effects that they experienced as follows: 0 = none, 1 = some or mild, 2 = moderate or medium, and 3 = severe.

We defined a complete medical abortion as any abortion that took place after administration of methotrexate and did not require suction curettage for any reason. If a woman was advised to have a curettage, but completed the abortion without curettage, we classified her as having a complete medical abortion. A complete abortion was documented when ultrasound demonstrated the disappearance of the gestational sac, or when the woman had a negative highly sensitive urine pregnancy test (threshold less than 50 mIU/mL ß-hCG), or when the staff examined the aborted tissue. If no gestational sac was seen at enrollment, a 90% drop in ß-hCG was considered evidence of completion. Undocumented outcomes included verbal reports from patients or providers.

We divided curettage outcomes into the following four groups: (1) patient option, curettage performed at the patient’s request; (2) day-14 failure, curettage performed because of a viable pregnancy 2 weeks after methotrexate (viability was assumed if there was embryonic cardiac activity); (3) day-28 failure, curettage performed because of the presence of any gestational sac 4 weeks after methotrexate; and (4) medically indicated curettage, curettage recommended by a physician for reasons other than abortion failure, such as excessive bleeding. Curettage for day-14 and day-28 failure and medically indicated curettage were considered indicated curettage.

Complications were classified as hemorrhage (blood loss of more than 500 mL as estimated by the investigator), postabortal infection, and any hospitalization.

During the study period, the only access to medical abortion was through the study. Thirty-two women requested repeated abortions and were permitted to enroll again. In this report only the first abortion for each woman is considered.

Health Decisions, Inc. (Chapel Hill, NC) performed database entry and verification.

We used SAS (SAS Institute, Cary, NC) for statistical analysis. The distribution of outcomes was examined with the Mantel-Haenszel {chi}2 test for categorical data and with analysis of variance for continuous variables. The Cochran test for trend was used when appropriate. A multiple logistic regression model was constructed to assess the probability of an adverse outcome (suction curettage) as a function of gestational age, patient age, pregnancy history, and site experience. Reported P values are two-tailed, and P < .05 was considered significant.


   Results
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Abstract
 Materials and Methods
 Results
Discussion
 References
 
Thirty-four sites enrolled 1973 women between October 1996 and July 1998. Characteristics of study women are shown in Table 1Go.


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  		Table 1. Characteristics of 1973 Women Who Requested Medical Abortion
 
Table 2Go summarizes the medical outcomes. Complete medical abortion was documented for 1589 women, and an additional 70 women reported complete abortion (1659 women, 84.1%). The date of abortion was reported by 1591 women; 69% aborted within the first week, and 79% aborted by 2 weeks.


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  		Table 2. Outcomes of Medical Abortion
 
The overall rate of suction curettage was 13%. Over two thirds of curettage was because of patient option (8.9% of all women). Twenty-nine women (1.4%) were advised to have curettage because of a viable pregnancy on study day 14. However, in at least two instances, embryonic growth was absent although embryonic cardiac activity persisted. Twenty-eight women had curettage completed between days 14 and 21. One women aborted without intervention before the scheduled curettage. There were no viable pregnancies beyond day 21.

Fifty-two women (2.6%) had not completed the abortion by day 28. Twenty-five women had curettage by day 29, and five women had curettage on day 35–44. Twenty-two women (1.1%) declined curettage and all aborted; 15 aborted within the subsequent 7 days.

Several factors were associated with curettage rates. Increasing gestational age at enrollment was correlated with higher rates of curettage, as seen in Figure 1Go (P < .004). The rate of patient option curettage was similar at each gestational age interval, approximately 10%. Indicated curettage increased from 0% at gestational ages of less than 35 days to 7.3% at 45 days or more (P < .001).



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  		Figure 1. Rates of suction curettage according to gestational age.

 
Prior pregnancy was also correlated with curettage rates (P < .004) (Figure 2Go). Women without prior pregnancies had the lowest rates of both optional (7.7%) and indicated curettage (2.7%). Women with prior abortion(s) only had intermediate rates, and women with prior births had the highest rates of optional (11.8%) and indicated curettage (6.4%). The odds ratio (OR) for curettage for women with a prior birth compared with never-pregnant women was 1.69 (95% confidence interval [CI] 1.17, 2.43). Both indicated curettage and optional curettage rates were higher in women with history of abortion or birth (P < .002 and P < .03, respectively).



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  		Figure 2. Rates of suction curettage according to pregnancy history.

 
Site experience with medical abortions was correlated with curettage rates. During the first 20 methotrexate abortions at each site, the rate of curettage was 17.0%. After the first 100 medical abortions, the rate was 9.9% (P < .006). The decrease in curettage rates was due to a decline in the optional curettage rate from 13.4% to 5.9% (P < .001).

Educational level, social or living situation, ethnic group, and use of public assistance were unrelated to outcomes. Younger women had fewer prior pregnancies, but patient age was not correlated to outcome when pregnancy history was taken into account. The presence of ultrasound landmarks did not show a pattern of correlation to curettage rate (Table 3Go). The day on which women took the first dose of misoprostol was not correlated with curettage rate (Table 3Go). Women who required only one dose of misoprostol had lower curettage rates than those taking two or three doses.


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  		Table 3. Curettage Rates According to Presence of Ultrasound Landmarks and Number and Timing of Misoprostol Doses
 
Adverse effects are summarized in Table 4Go. The duration of bleeding was known for 1303 women; 90% of women bled between 3 and 23 days, with a mean duration of 11.8 days. Most women (n = 1102) used one or more analgesic medications, including acetaminophen (n = 925), a nonsteroidal anti-inflammatory drug (n = 194), codeine (n = 602), and other oral narcotics (n = 68). One hundred forty-four women took antibiotics; the most frequent indications were bacterial vaginosis (n = 45) and prophylaxis (n = 44).


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  		Table 4. Summary of Adverse Effects
 
Ten women were hospitalized, three for more than 24 hours. One woman had an undiagnosed ectopic pregnancy requiring laparotomy and transfusion; this case was the only transfusion in this series. Her enrollment ultrasound was interpreted as an 8-mm intrauterine gestational sac. She was given methotrexate, and the ectopic pregnancy ruptured after vaginal misoprostol insertion. It is uncertain whether this was a misdiagnosis or a twin pregnancy.

Five women (0.25%) had vaginal bleeding estimated at more than 500 mL, all occurring 2 or more weeks after methotrexate administration. None were transfused. Four had curettage at the outpatient site, and one was hospitalized for curettage. Five other women were hospitalized at curettage for bleeding estimated at less than 500 mL; reasons for hospitalization included convenience and miscommunication.

One woman was hospitalized for several hours with gastrointestinal complaints. One woman had an exacerbation of long-quiescent inflammatory bowel disease. Two women had postabortal infections, one of whom was hospitalized. Two women had pneumonia within a month of abortion; one was hospitalized. Both cases appeared to be community-acquired bacterial infections with leukocytosis; neither woman had evidence of neutropenia or immunosuppression.


   Discussion
Top
Abstract
 Materials and Methods
 Results
 Discussion
References
 
Our findings confirm the efficacy and safety of methotrexate and misoprostol for medical abortion up to 7 weeks and provide support for the introduction of this method of abortion to community settings.

We found an overall efficacy rate for methotrexate plus misoprostol abortion of 84.1%, which is consistent with other studies that report rates of complete abortion from 83% to 97% by day 28.1–6 The incidence of adverse effects and duration of bleeding are consistent with other reports.2,3,11

Several factors were associated with curettage rates and, conversely, rates of complete medical abortion. The first factor was gestational age at methotrexate injection. Schaff et al3 suggested that before day 49, delayed abortion and bleeding are less frequent at earlier gestational ages. Our data support their findings. In terms of efficacy, we could not identify a minimum gestational age for use of methotrexate and misoprostol. Women who are interested in medical abortion should be encouraged to seek services as soon as they know they are pregnant.

The second factor affecting outcome was pregnancy history. Although parous women were more likely to request optional curettage, most of the increase in curettage rate was due to indicated curettage. These findings confirm and clarify those of Creinin et al,2 who noted that gravidity of less than three was associated with higher rates of complete medical abortion.

The third factor affecting outcome was site experience. The rate of curettage for patient option decreased as sites gained experience with methotrexate. Methotrexate plus misoprostol abortion can be an unpredictable process occurring over days or weeks, and virtually all women abort at home or outside of the medical care setting. As site staff gain confidence and experience, they might be able to provide better support to women who consider curettage. Also, staff might become better at selecting women who are more likely to complete the medical abortion process without intervention.

An apparently viable pregnancy 2 weeks after methotrexate administration persisted in 1.4% of women; however, several of the pregnancies had abnormal growth and probably were not viable. The failure rate for methotrexate-induced abortion might be lower than our report. In addition, 2–3% of women had a nonviable pregnancy that persisted a month after methotrexate. Half of those women declined curettage, and most aborted the following week. We believe that restricting the study period to 4 weeks is unnecessary; other investigators have reported longer observation periods.2,11

Serious complications were uncommon. Enrollment of one woman with an ectopic pregnancy emphasizes the need for caution in interpretation of ultrasound findings, before the appearance of a yolk sac or fetal pole. The rate of postabortal infection was low (0.1%), even in the absence of routine prophylactic antibiotics. The two women who had pneumonia had a clinical picture consistent with community-acquired pneumonia and did not have the pattern of pneumonitis reported in two women who had methotrexate treatment of ectopic pregnancy.12,13

Hospitalization for bleeding was rarely indicated; most of the hospitalized women could have been managed in the outpatient setting where the abortion was initiated. Some instances of bleeding could have been managed medically with uterotonic agents instead of curettage. There were several cases in which the physician recommended curettage on the basis of ultrasound findings of small amounts of intrauterine blood and debris; these are typical findings after medical abortion and do not require intervention.14 Recommendations for suction curettage should be based on clinical findings.

Therefore, our curettage rate of 13% could be reduced with the following changes: increasing site experience in patient selection and support, starting medical abortion at earlier gestational ages, eliminating the day-28 endpoint, refinements in medical management of bleeding, and more experience with ultrasound findings of medical abortion patients.

The process of methotrexate and misoprostol abortion allows for some variation in timing of medications and interventions without apparent effect on outcomes. Methotrexate and misoprostol abortion was effective and can safely be offered to women seeking care in a community outpatient care setting.


   Footnotes
 
Partial support for this project was provided by the Merck Foundation.

The views expressed herein do not necessarily represent the views of Planned Parenthood Federation of America, Inc.

We thank Olivera Vragovic, MBA, for her assistance with statistical analysis.

{dagger} Deceased. Back

PII S0029-7844(00)01090-5

Received April 4, 2000. Received in revised form July 17, 2000. Accepted July 20, 2000.


   References
Top
Abstract
 Materials and Methods
 Results
 Discussion
 References
 
1. Hausknecht RU. Methotrexate and misoprostol to terminate early pregnancy. N Engl J Med 1995;333:537–40.[Abstract/Free Full Text]

2. Creinin MD, Vittinghoff E, Keder L, Darney PD, Tiller GD. Methotrexate and misoprostol for early abortion: A multi-center trial. I. Safety and efficacy. Contraception 1996;53:321–7.[Medline]

3. Schaff EA, Eisinger SH, Franks P, Kim SS. Methotrexate and misoprostol for early abortion. Fam Med 1996;28:198–203.[Medline]

4. Wiebe ER. Abortion induced with methotrexate and misoprostol: A comparison of various protocols. Contraception 1997;55:159–63.[Medline]

5. Christin-Maitre S, Bouchard P, Spitz IM. Medical termination of pregnancy. N Engl J Med 2000;342:946–56.[Free Full Text]

6. Kahn JG, Becker BJ, MacIsaac L, Amory JK, Neuhaus J, Olkin I, et al. The efficacy of medical abortion: A meta-analysis. Contraception 2000;61:29–40.[Medline]

7. Spitz IM, Bardin W, Benton L, Robbins A. Early pregnancy termination with mifepristone and misoprostol in the United States. N Engl J Med 1998;338:1241–7.[Abstract/Free Full Text]

8. Weibe ER. Oral methotrexate compared with injected methotrexate when used with misoprostol for abortion. Am J Obstet Gynecol 1999;181:149–52.[Medline]

9. Goldstein SR, Wolfson R. Endovaginal ultrasonographic measurements of early embryonic size as a means of assessing gestational age. J Ultrasound Med 1994;13:27–31.[Abstract]

10. Rossavik IK, Torjusen GO, Gibbons WE. Conceptual age and ultrasound measurements of gestational sac and crown-rump length in in vitro fertilization pregnancies. Fertil Steril 1988;49: 1012–7.[Medline]

11. Creinin MD. Medical abortion with methotrexate 75 mg intramuscularly and vaginal misoprostol. Contraception 1997;56:367–71.[Medline]

12. Horrigan TJ, Fanning J, Marcotte MP. Methotrexate pneumonitis after systemic treatment for ectopic pregnancy. Am J Obstet Gynecol 1997;176:714–5.[Medline]

13. Schoenfeld A, Mashiach R, Vardy M, Ovadia J. Methotrexate pneumonitis in nonsurgical treatment of ectopic pregnancy. Obstet Gynecol 1992;80:520–1.[Abstract]

14. Creinin MD, Aubeny E. Medical abortion in early pregnancy. In: Paul M, Lichtenberg ES, Borgatta L, Grimes DA, Stubblefield PG, eds. A clinician’s guide to medical and surgical abortion. New York: Churchill Livingston, 1999:102–4.




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