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Efficacy and acceptability of a mifepristone–misoprostol combined regimen for early induced abortion among women in Mexico City
Efficacy and acceptability of a mifepristone–misoprostol combined regimen for early induced abortion among women in Mexico City Melanie Pe˜na, Ilana G. Dzuba, Patricio Sanhueza Smith, Luis Jorge Arellano Mendoza, Manuel Bousi´eguez, Mar´ıa Laura Garc´ıa Mart´ınez, Ranulfo R´ıos Polanco, Antonio Eduardo Flores Villal´on, Beverly Winikoff PII: DOI: Reference:
S0020-7292(14)00295-1 doi: 10.1016/j.ijgo.2014.04.012 IJG 7995
To appear in:
International Journal of Gynecology and Obstetrics
Received date: Revised date: Accepted date:
13 November 2013 6 April 2014 28 May 2014
Please cite this article as: Pe˜ na Melanie, Dzuba Ilana G., Smith Patricio Sanhueza, Mendoza Luis Jorge Arellano, Bousi´eguez Manuel, Mart´ınez Mar´ıa Laura Garc´ıa, Polanco Ranulfo R´ıos, Villal´ on Antonio Eduardo Flores, Winikoff Beverly, Efficacy and acceptability of a mifepristone–misoprostol combined regimen for early induced abortion among women in Mexico City, International Journal of Gynecology and Obstetrics (2014), doi: 10.1016/j.ijgo.2014.04.012
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT CLINICAL ARTICLE Efficacy and acceptability of a mifepristone–misoprostol combined regimen for
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early induced abortion among women in Mexico City
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Melanie Peña a,*, Ilana G. Dzuba a, Patricio Sanhueza Smith b, Luis Jorge Arellano
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Mendoza b, Manuel Bousiéguez c, María Laura García Martínez b, Ranulfo Ríos Polanco , Antonio Eduardo Flores Villalón b, Beverly Winikoff a
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b
Gynuity Health Projects, New York, USA
b
Secretariat of Health, Mexico City, Mexico
c
Independent consultant, Mexico City, Mexico
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a
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* Corresponding author: Melanie Peña Gynuity Health Projects, 15 East 26th Street, Suite 801, New York, NY 10010, USA. Tel.: +1 212 448 1230; fax: +1 212 448 1260. E-mail address: [email protected]
Keywords: Acceptability; Combined regimen; Efficacy; Medical abortion; Mexico; Mifepristone; Misoprostol
Synopsis: The use of a mifepristone–misoprostol combined regimen for early induced abortion in women attending public sector health facilities in Mexico City was found to be highly effective and acceptable.
ACCEPTED MANUSCRIPT ABSTRACT Objective: To evaluate the experience of women receiving mifepristone–misoprostol for
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early induced abortion in public sector facilities in the Federal District of Mexico City.
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Methods: An open-label prospective study was conducted with 1000 pregnant women who sought induced abortion with a pregnancy of up to 63 days of gestation, as
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measured from the date of their last menstrual period. The study was conducted in
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three public sector healthcare facilities: two secondary level hospitals and one primary care clinic. Women ingested 200 mg mifepristone on day 1, followed by 800 µg buccal
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misoprostol 24 hours later, and they returned for follow-up on day 8. The primary outcome was complete abortion without recourse to surgical intervention.
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Results: A total of 971 women received mifepristone–misoprostol and were included in the analysis for efficacy of treatment. The overall efficacy of the combined medical
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abortion regimen studied was 97.3% (n=945); the success rate did not vary significantly by gestational age (95.9%–100%; P=0.449). Most women (n=922, 95.0%) had a successful induced abortion with only one dose of misoprostol. Conclusion: The combined mifepristone and buccal misoprostol regimen was found to be highly effective and acceptable among Mexican women. www.ClinicalTrials.gov: NCT00386282.
ACCEPTED MANUSCRIPT 1. Introduction Elective induced abortion during the first 12 weeks of pregnancy was legalized in April
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2007 in the Federal District of Mexico. The new law prompted immediate action from the
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Secretariat of Health of Mexico City (SSDF) to provide legal induced abortion services in its facilities. Affiliated hospitals relied on dilatation and curettage (D&C) as the primary
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method of induced abortion, since obstetrician/gynecologists and general surgeons
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were already skilled in the procedure. The Secretariat recognized the potential of medical abortion technology to help meet the large demand for induced abortion
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services. To reduce the burden on the limited resources available for surgery, the SSDF started integrating medical methods of induced abortion. As of August 5, 2013, medical
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abortion accounted for 69% of elective induced abortions in the Secretariat system [1].
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Combined regimens of mifepristone and misoprostol remain the preferred method of medical abortion [2–5], but as mifepristone was not registered or available for distribution in Mexico in 2007, a misoprostol-only regimen was introduced initially.
The present article describes an open-label study of mifepristone–misoprostol medical abortion in SSDF facilities in Mexico City, designed to evaluate the efficacy, safety, and acceptability in this setting; to garner data that could be used for local registration of a 200-mg mifepristone product; and to provide training, access, and experience to healthcare providers with the best known medical method of induced abortion before large-scale introduction occurred.
ACCEPTED MANUSCRIPT The primary objective was to evaluate the effectiveness of the regimen of 200 mg mifepristone followed by 800 µg buccal misoprostol for induced abortion of pregnancies
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of up to 63 days of gestation in women seeking induced abortions at SSDF facilities.
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The efficacy and safety of this medical abortion regimen have been documented in clinical trials and retrospective studies involving over 12 000 women [3,4,6–8].
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Moreover, this regimen is the one most commonly used in the USA and is recognized
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by several health service delivery organizations and international guidance bodies including the National Abortion Federation [9], Planned Parenthood Federation of
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America (K. Shea, personal communication, May 16, 2012), the Royal College of Obstetricians and Gynaecologists [10], and WHO [5], among others. It was expected
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that the transition for clinical staff to this regimen would be simple as they were already
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employing an 800-µg buccal misoprostol-only regimen prior to study implementation.
2. Materials and methods
This open-label prospective study evaluated a combined regimen of 200 mg mifepristone followed by 800 µg buccal misoprostol in women with pregnancies of up to 63 days of gestation, as measured from the date of their last menstrual period. The study was conducted between September 28, 2010 and May 31, 2011 in three SSDF public sector healthcare facilities in Mexico City: two secondary level hospitals (Hospital General Enrique Cabrera and Hospital Materno-Infantil Inguarán) and one primary care clinic (Beatriz Velasco de Alemán). The protocol was approved by the Ethics, Biosecurity, and Research Commission of the Secretariat of Health of Mexico City and the Federal Commission for Protection against Sanitary Risks, the national drug
ACCEPTED MANUSCRIPT regulatory agency.
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Women were enrolled in the present study if they were interested in and eligible for
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medical abortion established in accordance with clinical evaluation and ultrasound exam, if they were willing to undergo surgical completion of abortion if needed, if they
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were willing to provide an address and/or telephone number for follow-up purposes, if
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they had access to a telephone and transport in case of an emergency, and if they consented to comply with the study procedures and visit schedule. Exclusion criteria
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followed labeled contraindications for mifepristone and misoprostol products. Gestational age was assessed from the date of the woman’s last menstrual period,
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clinical evaluation, and ultrasound.
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On day 1, participants swallowed one tablet of 200 mg mifepristone (Miffe; Linepharma, France) in the study center. Women were given 800 µg misoprostol (Cytotec; Pfizer, USA) to administer buccally at home 24 to 48 hours after mifepristone ingestion. They were instructed to place two pills in each cheek pouch and hold them in place, swallowing any remaining fragments after 30 minutes. All women were also given four 500-mg tablets of acetaminophen to take for pain as needed; providers were free to prescribe or recommend other medications at their discretion or if the participant requested additional analgesia. Women were advised to call the study team in case of concerns related to their induced abortion of pregnancy at any time. Participants were asked to return to the health center 8 days after study enrollment for a clinical exam and ultrasound as is standard care to determine the status of the abortion. Women with
ACCEPTED MANUSCRIPT continuing pregnancies underwent suction aspiration. Participants with nonviable pregnancies, such as persistent gestational sac, retained products of conception or
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bleeding, were offered a second dose of misoprostol, suction aspiration, or expectant
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management and were scheduled to return a week later for extended follow-up. Study participants who presented again with a persistent nonviable pregnancy at the extended
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follow-up visit underwent surgical completion. Suction evacuation was performed if the
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provider deemed it medically necessary, such as for problematic bleeding, or at the woman’s request. Women completed an exit interview prior to study discharge, to
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provide data on adverse effects and treatment acceptability. They rated their experience of pain during treatment using a visual seven-point Likert scale [11] that depicted a
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series of faces ranging from sad to neutral to happy. Study staff explained to women that each face represented a grade of pain severity, with the happiest face representing
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no pain and the saddest face representing the worst pain imaginable. The primary outcome of the study was success of the procedure as defined by complete abortion without recourse to surgical intervention for any reason. In addition, secondary outcomes included adverse effects experienced and method acceptability.
The sample size was calculated based on the published efficacy of 96% of the study regimen [9]. A comparable success rate was expected and thus it was determined that a sample of 500 participants would suffice to document 95% efficacy with a 95% confidence interval of ± 2%. The sample size was increased to account for loss to follow-up (estimated at 15%) and heterogeneity in research sites, personnel, and patient populations. Frequencies and means (with standard deviations) were calculated using
ACCEPTED MANUSCRIPT SPSS 19.0 (IBM, Armonk, NY, USA) and were evaluated by intention-to-treat analysis. Treatment adherence and abortion status were ascertained at follow-up in the study
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center or by telephone.
3. Results
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One thousand women were enrolled in the study (Table 1). Twenty-nine (2.9%) women
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did not return for their follow-up visits and could not be reached by telephone by study personnel. Thus, 971 participants were followed up and their results were analyzed for
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efficacy. Two women were mistakenly enrolled with pregnancies of more than 63 days of gestation as measured from the date of their last menstrual period. In accordance
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with the intention-to-treat analysis, their outcomes (each had a successful induced abortion with study medications alone) were included in the analysis. The overall
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efficacy of the combined medical abortion regimen studied was 97.3% (n=945); the success rate did not vary significantly by gestational age (95.9%–100%; P=0.449) (Table 2). Most women (94.9%, n=922) had a successful induced abortion with only one dose of misoprostol. There were a total of 26 surgical evacuations (2.7%); the reported reason for the majority of surgical evacuations was bleeding (n=16, 1.7%). Few women experienced continuing pregnancy (n=6, 0.6%) or persistent sac (n=2, 0.2%); an additional two women (0.2%) received surgical intervention for pain.
A total of 858 (88.5%) women reported adverse effects (Figure 1). Diarrhea and fever/chills were the most commonly reported adverse effects, followed by nausea and
ACCEPTED MANUSCRIPT vomiting. Fever/chills (n=86, 8.9%) and diarrhea (n=76, 7.8%) were most commonly
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reported by participants as severe. The mean pain score reported was 5.1 (range 1–7).
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Of the women who took the study regimen, 38 (3.8%) placed telephone calls to the study team during their participation in the study; of those, the vast majority (n=34,
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89.5%) called only once. Two women (0.2%) made unscheduled visits to the study
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centers. Seventeen study participants (1.7%) visited other health facilities, primarily for bleeding or pain or a combination of the two (n=13), followed by anxiety (n=2), and
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fainting or tachycardia (n=2). Twelve women treated in non-study facilities underwent D&C, three were verbally reassured and received no additional treatment, and two
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women were offered but refused D&C and did not report any adverse effects. There were no serious complications as defined by any occurrence that was unexpected,
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serious, and related to the induced abortion.
Almost all women (n=915, 94.4%) reported they were satisfied with their treatment, and most participants (n=778, 80.3%) reported that the adverse effects were acceptable (Table 3). Women were able to report up to two positive and two negative aspects of the treatment. The most commonly mentioned positive aspects of the medical abortion procedure were the rapidity of the treatment (n=410/1118, 36.7%) and its efficacy (n=279/1118, 25.0%). About one-third of women (n=337, 34.8%) did not report any negative aspect of treatment. Cramps and pain were reported as the worst aspect of this treatment (n=380/1054, 36.1%), with 46.0% (n=446) noting that the pain was greater than expected (Table 4). Even so, 88.8% (n=860) of all women reported they
ACCEPTED MANUSCRIPT would have another medical abortion in the future if the situation arose. The vast majority of women (n=700, 72.2%) perceived that bleeding was less than or as
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expected (Table 4).
4. Discussion
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The effectiveness and acceptability of the medical abortion regimen used in the present
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study were consistent with those reported in the published literature [6,7]. Adverse effects were also comparable for most measures with those reported in other studies
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that used the same regimen [3,6]. Although women who undergo medical abortion are typically highly satisfied with the treatment and would recommend it to others, pain is
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often cited as the worst feature of the procedure, no matter what regimen of pain control
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is used [12]. This was also true for women in the present study. Women’s analgesic use
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was not documented, however, so it was not possible to associate it with pain scores. Notwithstanding, the high level of pain reported on the visual analog scale and the relatively high proportion of women who reported pain being greater than they expected indicates that there may be room for improved pain management. There is little consensus about the most efficacious pain relief regimen for first-trimester medical abortion and research is continuing to inform service delivery practice on pain management [13].
The high level of satisfaction with the treatment reported by women in the present study is also strongly consistent with the published literature. Previous research has explored the acceptability of medical abortion by women, especially relating to aspects such as
ACCEPTED MANUSCRIPT increased privacy and autonomy, and the less invasive nature of the procedure compared with surgical alternatives [14]. Satisfaction with these aspects of medical
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abortion treatment appears to be almost universal and has been reported for diverse
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populations [12]. Research has also documented that satisfaction is highly correlated
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with induced abortion success, which were both high in the present study [12].
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It is possible that patient satisfaction may also be influenced by provider acceptability of medical methods. Within the first year of the legal induced abortion program in Mexico
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City providers made a swift transition to medical abortion. A qualitative study reported that healthcare professionals believed medical abortion resulted in a decrease in
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workload and possibly fewer conscientious objectors [15]. The very low number of calls
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and unscheduled visits to the study sites in the present study may reflect women’s
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preparedness for what was to occur and their level of trust in the services. This phenomenon may also be indicative of the confidence that the study team had in the method, since these clinical providers and counselors already had previous experience with administering misoprostol-only regimens.
A mifepristone product was registered in Mexico in March 2011 and has been used in Secretariat facilities since December 2011. The mifepristone product currently available is relatively costly, however, the total cost of the drugs for the mifepristone and misoprostol regimen and misoprostol-only regimen previously used by the SSDF are essentially equivalent because of the high cost of misoprostol in Mexico. In reality, the combined regimen is less expensive than misoprostol-only regimens, however, as the
ACCEPTED MANUSCRIPT method is more effective and therefore saves personnel and other treatment costs associated with aspirations for failed misoprostol-only procedures. In May 2013, a
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second mifepristone product was registered and it is hoped that this additional product
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will help to reduce costs further. Registration of additional mifepristone products can reduce the cost of mifepristone and thus increase access in both public and private
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sectors. Ideally, combined mifepristone and misoprostol medical abortion regimens
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should be offered in all settings.
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Since study completion, the SSDF has adapted its mifepristone abortion protocol to include recent documented innovations including home administration of mifepristone
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of pregnancy [17].
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[16] and outpatient induced abortions with the same regimen during the first 10 weeks
The liberalization of the induced abortion law in the Federal District of Mexico has created an unusual situation that has implications for all Mexican citizens. Any woman is legally allowed to receive an abortion in Mexico City, although limitations still exist for those who cannot afford the journey or the cost of services. Notwithstanding, for many women the ability to obtain safe and legal induced abortion reduces the risk of complications (including sepsis, perforated uterus, damaged cervix, death, among others) more often associated with the restricted legal context that exists in the rest of the country. The rapidity with which a medical abortion protocol was introduced into public sector services is a groundbreaking example for the region, benefitting the health system and women alike. The introduction of a medical abortion protocol has helped the
ACCEPTED MANUSCRIPT Secretariat meet a growing demand that could not easily be accommodated by surgical abortion alone and has relieved the burden on the limited number of induced abortion
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providers operating during the first year after legalization. The present study helped
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prepare public health sector providers to transition from a misoprostol-only regimen to a combined regimen once mifepristone was registered and available on the market. Now
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more than a year since mifepristone was made available in Mexico, the gold standard of
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treatment using a combined regimen of mifepristone and misoprostol is firmly
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established as the primary method for induced abortion of early pregnancy.
Acknowledgments
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Conflict of interest
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The study was funded by a grant from an anonymous donor.
The authors have no conflicts of interest.
ACCEPTED MANUSCRIPT References [1]
Health Information Management, General Management of Planning and
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Coordination Sector, Mexico City Ministry of Health. Extract of Patient Registration of
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the Legal Termination of Pregnancy Program. Published 2013.
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Ngoc NTN, Blum J, Raghavan S, Nga NTB, Dabash R, Diop A, et al. Comparing
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[3]
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methods for first trimester abortion. Cochrane Database Syst Rev 2011;(11):CD002855.
Contraception 2011;83(5):410–7. [4]
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two early medical abortion regimens: mifepristone+misoprostol vs. misoprostol alone.
Blum J, Raghavan S, Dabash R, Ngoc NTN, Chelli H, Hajri S, et al. Comparison
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of misoprostol-only and combined mifepristone–misoprostol regimens for home-based early medical abortion in Tunisia and Vietnam. Int J Gynecol Obstet 2012;118(2):166–
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Health Systems. Second Edition. http://apps.who.int/iris/bitstream/10665/70914/1/9789241548434_eng.pdf. Published 2012. Accessed October 23, 2013. [6]
Winikoff B, Dzuba IG, Creinin MD, Crowden WA, Goldberg AB, Gonzales J, et al.
Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial. Obstet Gynecol 2008;112(6):1303–10. [7]
Chong E, Tsereteli T, Nguyen NN, Winikoff B. A randomized controlled trial of
different buccal misoprostol doses in mifepristone medical abortion. Contraception 2012;86(3):251–25.
ACCEPTED MANUSCRIPT [8]
Goldstone P, Michelson J, Williamson E. Early medical abortion using low-dose
mifepristone followed by buccal misoprostol: a large Australian observational study.
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[9]
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Med J Aust 2012;197(5):282–6.
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Hoboken, NJ: John Wiley & Sons; 2009.
Requesting Induced Abortion: Evidence-based Clinical Guideline Number 7.
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http://www.rcog.org.uk/files/rcog-corp/Abortion%20guideline_web_1.pdf. Published November 2011. Accessed October 23, 2013.
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Likert R. A technique for the measurement of attitudes. Arch Psychol
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Swica Y, Raghavan S, Bracken H, Dabash R, Winikoff B. Review of the literature
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on patient satisfaction with early medical abortion using mifepristone and misoprostol. Expert Rev Obstet Gynecol 2011;6(4):451–68. [13]
Raymond EG, Weaver MA, Louie KS, Dean G, Porsch L, Lichtenberg ES, et al.
Prophylactic compared with therapeutic Ibuprofen analgesia in first-trimester medical abortion. Obstet Gynecol 2013;122(3):558–64. [14]
Lafaurie MM, Grossman D, Troncoso E, Billings DL, Chávez S. Women's
perspectives on medical abortion in Mexico, Colombia, Ecuador and Peru: a qualitative study. Reprod Health Matters 2005;13(26):75–83.
ACCEPTED MANUSCRIPT [15]
Contreras X, van Dijk MG, Sanchez T, Smith PS. Experiences and opinions of
health-care professionals regarding legal abortion in Mexico City: a qualitative study.
Swica Y, Chong E, Middleton T, Prine L, Gold M, Schreiber CA, et al.
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Stud Fam Plann 2011;42(3):183–90.
Acceptability of home use of mifepristone for medical abortion. Contraception
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2013;88(1):122–7.
Extending outpatient medical abortion services through 70 days of gestational age.
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Obstet Gynecol 2012;120(5):1070–6.
ACCEPTED MANUSCRIPT Figure 1 Adverse effects and degree of severity reported by participants at follow-up (n=969).a Two participants did not complete the exit interview.
b
Missing level of severity for 1 participant.
c
Missing level of severity for 1 participant.
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Other reported adverse effects included: anxiety/irritability/depression, dry throat, rash,
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hypotension, flu, difficulty breathing, hands fell asleep, and hunger.
ACCEPTED MANUSCRIPT Table 1 Characteristics of women undergoing medical abortion in Mexico City (n=1000). Data
Age, y
25.4 (13–45)
Gravidity
2.3 (1–7)
Women reporting any previous induced abortion
97 (9.7)
Women reporting any previous medical abortion
74 (7.4)
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Characteristic
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Gestational age in days <49
569 (56.9)
50–56
252 (25.2)
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57–63 >64
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Values are given as mean (range) or number (percentage).
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177 (17.7) 2 (0.2)
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Table 2 Treatment efficacy by gestational age in days. <49 50–56 (n=551) (n=247)
57–63 (n=171)
>64 (n=2)
Total (n=971)
2 (100)
945 (97.3)
540 (98.0)
239 (96.8)
164 (95.9)
Surgical evacuation
11 (2.0)
8 (3.2)
7 (4.1)
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2 (1.2) 1 (0.6) 4 (2.3) --
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Reason for evacuation Continuing pregnancy 3 (0.6) 1 (0.4) Persistent sac -1 (0.4) Bleeding 6 (1.1) 6 (2.4) c Other 2 (0.4) -a Values are given as number (percentage). b Does not include women lost to follow-up (n=29). c Reason indicated was pain.
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Success
--
26 (2.7)
-----
6 (0.6) 2 (0.2) 16 (1.7) 2 (0.2)
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Satisfaction with treatment Satisfactory 915 (94.4) Neutral 27 (2.8) Unsatisfactory 27 (2.8) a Two participants did not complete the exit interview.
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Table 3 Acceptability of adverse effects and satisfaction with method of induced abortion (n=969). No. (%) Adverse effects Acceptable 778 (80.3) Neutral 146 (15.1) Unacceptable 32 (3.3) Don't know 13 (1.3)
a
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Table 4 Levels of pain and bleeding during treatment compared with women’s expectations (n=969). Pain Bleeding No. (%) No. (%) Less than expected 255 (26.3) 296 (30.5) As expected 261 (26.9) 404 (41.7) More than expected 446 (46.0) 262 (27.0) Don't know 7 (0. 7) 7 (0.7) a Two participants did not complete the exit interview.
a
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Figure 1
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ACCEPTED MANUSCRIPT
S0020-7292(14)00295-1 doi: 10.1016/j.ijgo.2014.04.012 IJG 7995
To appear in:
International Journal of Gynecology and Obstetrics
Received date: Revised date: Accepted date:
13 November 2013 6 April 2014 28 May 2014
Please cite this article as: Pe˜ na Melanie, Dzuba Ilana G., Smith Patricio Sanhueza, Mendoza Luis Jorge Arellano, Bousi´eguez Manuel, Mart´ınez Mar´ıa Laura Garc´ıa, Polanco Ranulfo R´ıos, Villal´ on Antonio Eduardo Flores, Winikoff Beverly, Efficacy and acceptability of a mifepristone–misoprostol combined regimen for early induced abortion among women in Mexico City, International Journal of Gynecology and Obstetrics (2014), doi: 10.1016/j.ijgo.2014.04.012
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT CLINICAL ARTICLE Efficacy and acceptability of a mifepristone–misoprostol combined regimen for
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early induced abortion among women in Mexico City
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Melanie Peña a,*, Ilana G. Dzuba a, Patricio Sanhueza Smith b, Luis Jorge Arellano
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Mendoza b, Manuel Bousiéguez c, María Laura García Martínez b, Ranulfo Ríos Polanco , Antonio Eduardo Flores Villalón b, Beverly Winikoff a
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b
Gynuity Health Projects, New York, USA
b
Secretariat of Health, Mexico City, Mexico
c
Independent consultant, Mexico City, Mexico
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a
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* Corresponding author: Melanie Peña Gynuity Health Projects, 15 East 26th Street, Suite 801, New York, NY 10010, USA. Tel.: +1 212 448 1230; fax: +1 212 448 1260. E-mail address: [email protected]
Keywords: Acceptability; Combined regimen; Efficacy; Medical abortion; Mexico; Mifepristone; Misoprostol
Synopsis: The use of a mifepristone–misoprostol combined regimen for early induced abortion in women attending public sector health facilities in Mexico City was found to be highly effective and acceptable.
ACCEPTED MANUSCRIPT ABSTRACT Objective: To evaluate the experience of women receiving mifepristone–misoprostol for
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early induced abortion in public sector facilities in the Federal District of Mexico City.
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Methods: An open-label prospective study was conducted with 1000 pregnant women who sought induced abortion with a pregnancy of up to 63 days of gestation, as
SC
measured from the date of their last menstrual period. The study was conducted in
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three public sector healthcare facilities: two secondary level hospitals and one primary care clinic. Women ingested 200 mg mifepristone on day 1, followed by 800 µg buccal
MA
misoprostol 24 hours later, and they returned for follow-up on day 8. The primary outcome was complete abortion without recourse to surgical intervention.
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Results: A total of 971 women received mifepristone–misoprostol and were included in the analysis for efficacy of treatment. The overall efficacy of the combined medical
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abortion regimen studied was 97.3% (n=945); the success rate did not vary significantly by gestational age (95.9%–100%; P=0.449). Most women (n=922, 95.0%) had a successful induced abortion with only one dose of misoprostol. Conclusion: The combined mifepristone and buccal misoprostol regimen was found to be highly effective and acceptable among Mexican women. www.ClinicalTrials.gov: NCT00386282.
ACCEPTED MANUSCRIPT 1. Introduction Elective induced abortion during the first 12 weeks of pregnancy was legalized in April
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2007 in the Federal District of Mexico. The new law prompted immediate action from the
RI
Secretariat of Health of Mexico City (SSDF) to provide legal induced abortion services in its facilities. Affiliated hospitals relied on dilatation and curettage (D&C) as the primary
SC
method of induced abortion, since obstetrician/gynecologists and general surgeons
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were already skilled in the procedure. The Secretariat recognized the potential of medical abortion technology to help meet the large demand for induced abortion
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services. To reduce the burden on the limited resources available for surgery, the SSDF started integrating medical methods of induced abortion. As of August 5, 2013, medical
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abortion accounted for 69% of elective induced abortions in the Secretariat system [1].
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Combined regimens of mifepristone and misoprostol remain the preferred method of medical abortion [2–5], but as mifepristone was not registered or available for distribution in Mexico in 2007, a misoprostol-only regimen was introduced initially.
The present article describes an open-label study of mifepristone–misoprostol medical abortion in SSDF facilities in Mexico City, designed to evaluate the efficacy, safety, and acceptability in this setting; to garner data that could be used for local registration of a 200-mg mifepristone product; and to provide training, access, and experience to healthcare providers with the best known medical method of induced abortion before large-scale introduction occurred.
ACCEPTED MANUSCRIPT The primary objective was to evaluate the effectiveness of the regimen of 200 mg mifepristone followed by 800 µg buccal misoprostol for induced abortion of pregnancies
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of up to 63 days of gestation in women seeking induced abortions at SSDF facilities.
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The efficacy and safety of this medical abortion regimen have been documented in clinical trials and retrospective studies involving over 12 000 women [3,4,6–8].
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Moreover, this regimen is the one most commonly used in the USA and is recognized
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by several health service delivery organizations and international guidance bodies including the National Abortion Federation [9], Planned Parenthood Federation of
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America (K. Shea, personal communication, May 16, 2012), the Royal College of Obstetricians and Gynaecologists [10], and WHO [5], among others. It was expected
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that the transition for clinical staff to this regimen would be simple as they were already
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employing an 800-µg buccal misoprostol-only regimen prior to study implementation.
2. Materials and methods
This open-label prospective study evaluated a combined regimen of 200 mg mifepristone followed by 800 µg buccal misoprostol in women with pregnancies of up to 63 days of gestation, as measured from the date of their last menstrual period. The study was conducted between September 28, 2010 and May 31, 2011 in three SSDF public sector healthcare facilities in Mexico City: two secondary level hospitals (Hospital General Enrique Cabrera and Hospital Materno-Infantil Inguarán) and one primary care clinic (Beatriz Velasco de Alemán). The protocol was approved by the Ethics, Biosecurity, and Research Commission of the Secretariat of Health of Mexico City and the Federal Commission for Protection against Sanitary Risks, the national drug
ACCEPTED MANUSCRIPT regulatory agency.
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Women were enrolled in the present study if they were interested in and eligible for
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medical abortion established in accordance with clinical evaluation and ultrasound exam, if they were willing to undergo surgical completion of abortion if needed, if they
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were willing to provide an address and/or telephone number for follow-up purposes, if
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they had access to a telephone and transport in case of an emergency, and if they consented to comply with the study procedures and visit schedule. Exclusion criteria
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followed labeled contraindications for mifepristone and misoprostol products. Gestational age was assessed from the date of the woman’s last menstrual period,
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clinical evaluation, and ultrasound.
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On day 1, participants swallowed one tablet of 200 mg mifepristone (Miffe; Linepharma, France) in the study center. Women were given 800 µg misoprostol (Cytotec; Pfizer, USA) to administer buccally at home 24 to 48 hours after mifepristone ingestion. They were instructed to place two pills in each cheek pouch and hold them in place, swallowing any remaining fragments after 30 minutes. All women were also given four 500-mg tablets of acetaminophen to take for pain as needed; providers were free to prescribe or recommend other medications at their discretion or if the participant requested additional analgesia. Women were advised to call the study team in case of concerns related to their induced abortion of pregnancy at any time. Participants were asked to return to the health center 8 days after study enrollment for a clinical exam and ultrasound as is standard care to determine the status of the abortion. Women with
ACCEPTED MANUSCRIPT continuing pregnancies underwent suction aspiration. Participants with nonviable pregnancies, such as persistent gestational sac, retained products of conception or
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bleeding, were offered a second dose of misoprostol, suction aspiration, or expectant
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management and were scheduled to return a week later for extended follow-up. Study participants who presented again with a persistent nonviable pregnancy at the extended
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follow-up visit underwent surgical completion. Suction evacuation was performed if the
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provider deemed it medically necessary, such as for problematic bleeding, or at the woman’s request. Women completed an exit interview prior to study discharge, to
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provide data on adverse effects and treatment acceptability. They rated their experience of pain during treatment using a visual seven-point Likert scale [11] that depicted a
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series of faces ranging from sad to neutral to happy. Study staff explained to women that each face represented a grade of pain severity, with the happiest face representing
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no pain and the saddest face representing the worst pain imaginable. The primary outcome of the study was success of the procedure as defined by complete abortion without recourse to surgical intervention for any reason. In addition, secondary outcomes included adverse effects experienced and method acceptability.
The sample size was calculated based on the published efficacy of 96% of the study regimen [9]. A comparable success rate was expected and thus it was determined that a sample of 500 participants would suffice to document 95% efficacy with a 95% confidence interval of ± 2%. The sample size was increased to account for loss to follow-up (estimated at 15%) and heterogeneity in research sites, personnel, and patient populations. Frequencies and means (with standard deviations) were calculated using
ACCEPTED MANUSCRIPT SPSS 19.0 (IBM, Armonk, NY, USA) and were evaluated by intention-to-treat analysis. Treatment adherence and abortion status were ascertained at follow-up in the study
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center or by telephone.
3. Results
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One thousand women were enrolled in the study (Table 1). Twenty-nine (2.9%) women
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did not return for their follow-up visits and could not be reached by telephone by study personnel. Thus, 971 participants were followed up and their results were analyzed for
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efficacy. Two women were mistakenly enrolled with pregnancies of more than 63 days of gestation as measured from the date of their last menstrual period. In accordance
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with the intention-to-treat analysis, their outcomes (each had a successful induced abortion with study medications alone) were included in the analysis. The overall
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efficacy of the combined medical abortion regimen studied was 97.3% (n=945); the success rate did not vary significantly by gestational age (95.9%–100%; P=0.449) (Table 2). Most women (94.9%, n=922) had a successful induced abortion with only one dose of misoprostol. There were a total of 26 surgical evacuations (2.7%); the reported reason for the majority of surgical evacuations was bleeding (n=16, 1.7%). Few women experienced continuing pregnancy (n=6, 0.6%) or persistent sac (n=2, 0.2%); an additional two women (0.2%) received surgical intervention for pain.
A total of 858 (88.5%) women reported adverse effects (Figure 1). Diarrhea and fever/chills were the most commonly reported adverse effects, followed by nausea and
ACCEPTED MANUSCRIPT vomiting. Fever/chills (n=86, 8.9%) and diarrhea (n=76, 7.8%) were most commonly
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reported by participants as severe. The mean pain score reported was 5.1 (range 1–7).
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Of the women who took the study regimen, 38 (3.8%) placed telephone calls to the study team during their participation in the study; of those, the vast majority (n=34,
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89.5%) called only once. Two women (0.2%) made unscheduled visits to the study
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centers. Seventeen study participants (1.7%) visited other health facilities, primarily for bleeding or pain or a combination of the two (n=13), followed by anxiety (n=2), and
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fainting or tachycardia (n=2). Twelve women treated in non-study facilities underwent D&C, three were verbally reassured and received no additional treatment, and two
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women were offered but refused D&C and did not report any adverse effects. There were no serious complications as defined by any occurrence that was unexpected,
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serious, and related to the induced abortion.
Almost all women (n=915, 94.4%) reported they were satisfied with their treatment, and most participants (n=778, 80.3%) reported that the adverse effects were acceptable (Table 3). Women were able to report up to two positive and two negative aspects of the treatment. The most commonly mentioned positive aspects of the medical abortion procedure were the rapidity of the treatment (n=410/1118, 36.7%) and its efficacy (n=279/1118, 25.0%). About one-third of women (n=337, 34.8%) did not report any negative aspect of treatment. Cramps and pain were reported as the worst aspect of this treatment (n=380/1054, 36.1%), with 46.0% (n=446) noting that the pain was greater than expected (Table 4). Even so, 88.8% (n=860) of all women reported they
ACCEPTED MANUSCRIPT would have another medical abortion in the future if the situation arose. The vast majority of women (n=700, 72.2%) perceived that bleeding was less than or as
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expected (Table 4).
4. Discussion
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The effectiveness and acceptability of the medical abortion regimen used in the present
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study were consistent with those reported in the published literature [6,7]. Adverse effects were also comparable for most measures with those reported in other studies
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that used the same regimen [3,6]. Although women who undergo medical abortion are typically highly satisfied with the treatment and would recommend it to others, pain is
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often cited as the worst feature of the procedure, no matter what regimen of pain control
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is used [12]. This was also true for women in the present study. Women’s analgesic use
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was not documented, however, so it was not possible to associate it with pain scores. Notwithstanding, the high level of pain reported on the visual analog scale and the relatively high proportion of women who reported pain being greater than they expected indicates that there may be room for improved pain management. There is little consensus about the most efficacious pain relief regimen for first-trimester medical abortion and research is continuing to inform service delivery practice on pain management [13].
The high level of satisfaction with the treatment reported by women in the present study is also strongly consistent with the published literature. Previous research has explored the acceptability of medical abortion by women, especially relating to aspects such as
ACCEPTED MANUSCRIPT increased privacy and autonomy, and the less invasive nature of the procedure compared with surgical alternatives [14]. Satisfaction with these aspects of medical
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abortion treatment appears to be almost universal and has been reported for diverse
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populations [12]. Research has also documented that satisfaction is highly correlated
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with induced abortion success, which were both high in the present study [12].
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It is possible that patient satisfaction may also be influenced by provider acceptability of medical methods. Within the first year of the legal induced abortion program in Mexico
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City providers made a swift transition to medical abortion. A qualitative study reported that healthcare professionals believed medical abortion resulted in a decrease in
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workload and possibly fewer conscientious objectors [15]. The very low number of calls
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and unscheduled visits to the study sites in the present study may reflect women’s
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preparedness for what was to occur and their level of trust in the services. This phenomenon may also be indicative of the confidence that the study team had in the method, since these clinical providers and counselors already had previous experience with administering misoprostol-only regimens.
A mifepristone product was registered in Mexico in March 2011 and has been used in Secretariat facilities since December 2011. The mifepristone product currently available is relatively costly, however, the total cost of the drugs for the mifepristone and misoprostol regimen and misoprostol-only regimen previously used by the SSDF are essentially equivalent because of the high cost of misoprostol in Mexico. In reality, the combined regimen is less expensive than misoprostol-only regimens, however, as the
ACCEPTED MANUSCRIPT method is more effective and therefore saves personnel and other treatment costs associated with aspirations for failed misoprostol-only procedures. In May 2013, a
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second mifepristone product was registered and it is hoped that this additional product
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will help to reduce costs further. Registration of additional mifepristone products can reduce the cost of mifepristone and thus increase access in both public and private
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sectors. Ideally, combined mifepristone and misoprostol medical abortion regimens
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should be offered in all settings.
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Since study completion, the SSDF has adapted its mifepristone abortion protocol to include recent documented innovations including home administration of mifepristone
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of pregnancy [17].
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[16] and outpatient induced abortions with the same regimen during the first 10 weeks
The liberalization of the induced abortion law in the Federal District of Mexico has created an unusual situation that has implications for all Mexican citizens. Any woman is legally allowed to receive an abortion in Mexico City, although limitations still exist for those who cannot afford the journey or the cost of services. Notwithstanding, for many women the ability to obtain safe and legal induced abortion reduces the risk of complications (including sepsis, perforated uterus, damaged cervix, death, among others) more often associated with the restricted legal context that exists in the rest of the country. The rapidity with which a medical abortion protocol was introduced into public sector services is a groundbreaking example for the region, benefitting the health system and women alike. The introduction of a medical abortion protocol has helped the
ACCEPTED MANUSCRIPT Secretariat meet a growing demand that could not easily be accommodated by surgical abortion alone and has relieved the burden on the limited number of induced abortion
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providers operating during the first year after legalization. The present study helped
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prepare public health sector providers to transition from a misoprostol-only regimen to a combined regimen once mifepristone was registered and available on the market. Now
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more than a year since mifepristone was made available in Mexico, the gold standard of
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treatment using a combined regimen of mifepristone and misoprostol is firmly
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established as the primary method for induced abortion of early pregnancy.
Acknowledgments
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Conflict of interest
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The study was funded by a grant from an anonymous donor.
The authors have no conflicts of interest.
ACCEPTED MANUSCRIPT References [1]
Health Information Management, General Management of Planning and
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Coordination Sector, Mexico City Ministry of Health. Extract of Patient Registration of
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the Legal Termination of Pregnancy Program. Published 2013.
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methods for first trimester abortion. Cochrane Database Syst Rev 2011;(11):CD002855.
Contraception 2011;83(5):410–7. [4]
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Blum J, Raghavan S, Dabash R, Ngoc NTN, Chelli H, Hajri S, et al. Comparison
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of misoprostol-only and combined mifepristone–misoprostol regimens for home-based early medical abortion in Tunisia and Vietnam. Int J Gynecol Obstet 2012;118(2):166–
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Chong E, Tsereteli T, Nguyen NN, Winikoff B. A randomized controlled trial of
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ACCEPTED MANUSCRIPT [8]
Goldstone P, Michelson J, Williamson E. Early medical abortion using low-dose
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Hoboken, NJ: John Wiley & Sons; 2009.
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http://www.rcog.org.uk/files/rcog-corp/Abortion%20guideline_web_1.pdf. Published November 2011. Accessed October 23, 2013.
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on patient satisfaction with early medical abortion using mifepristone and misoprostol. Expert Rev Obstet Gynecol 2011;6(4):451–68. [13]
Raymond EG, Weaver MA, Louie KS, Dean G, Porsch L, Lichtenberg ES, et al.
Prophylactic compared with therapeutic Ibuprofen analgesia in first-trimester medical abortion. Obstet Gynecol 2013;122(3):558–64. [14]
Lafaurie MM, Grossman D, Troncoso E, Billings DL, Chávez S. Women's
perspectives on medical abortion in Mexico, Colombia, Ecuador and Peru: a qualitative study. Reprod Health Matters 2005;13(26):75–83.
ACCEPTED MANUSCRIPT [15]
Contreras X, van Dijk MG, Sanchez T, Smith PS. Experiences and opinions of
health-care professionals regarding legal abortion in Mexico City: a qualitative study.
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Extending outpatient medical abortion services through 70 days of gestational age.
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ACCEPTED MANUSCRIPT Figure 1 Adverse effects and degree of severity reported by participants at follow-up (n=969).a Two participants did not complete the exit interview.
b
Missing level of severity for 1 participant.
c
Missing level of severity for 1 participant.
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Other reported adverse effects included: anxiety/irritability/depression, dry throat, rash,
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a
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hypotension, flu, difficulty breathing, hands fell asleep, and hunger.
ACCEPTED MANUSCRIPT Table 1 Characteristics of women undergoing medical abortion in Mexico City (n=1000). Data
Age, y
25.4 (13–45)
Gravidity
2.3 (1–7)
Women reporting any previous induced abortion
97 (9.7)
Women reporting any previous medical abortion
74 (7.4)
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Characteristic
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Gestational age in days <49
569 (56.9)
50–56
252 (25.2)
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57–63 >64
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Values are given as mean (range) or number (percentage).
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177 (17.7) 2 (0.2)
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Table 2 Treatment efficacy by gestational age in days. <49 50–56 (n=551) (n=247)
57–63 (n=171)
>64 (n=2)
Total (n=971)
2 (100)
945 (97.3)
540 (98.0)
239 (96.8)
164 (95.9)
Surgical evacuation
11 (2.0)
8 (3.2)
7 (4.1)
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2 (1.2) 1 (0.6) 4 (2.3) --
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Reason for evacuation Continuing pregnancy 3 (0.6) 1 (0.4) Persistent sac -1 (0.4) Bleeding 6 (1.1) 6 (2.4) c Other 2 (0.4) -a Values are given as number (percentage). b Does not include women lost to follow-up (n=29). c Reason indicated was pain.
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Success
--
26 (2.7)
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6 (0.6) 2 (0.2) 16 (1.7) 2 (0.2)
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Satisfaction with treatment Satisfactory 915 (94.4) Neutral 27 (2.8) Unsatisfactory 27 (2.8) a Two participants did not complete the exit interview.
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Table 3 Acceptability of adverse effects and satisfaction with method of induced abortion (n=969). No. (%) Adverse effects Acceptable 778 (80.3) Neutral 146 (15.1) Unacceptable 32 (3.3) Don't know 13 (1.3)
a
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Table 4 Levels of pain and bleeding during treatment compared with women’s expectations (n=969). Pain Bleeding No. (%) No. (%) Less than expected 255 (26.3) 296 (30.5) As expected 261 (26.9) 404 (41.7) More than expected 446 (46.0) 262 (27.0) Don't know 7 (0. 7) 7 (0.7) a Two participants did not complete the exit interview.
a
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Figure 1
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