Choices for Medical Abortion Introduction in Brazil, Colombia, Mexico and Peru

Choices for Medical Abortion Introduction in Brazil, Colombia, Mexico and Peru

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Table of Contents
I – Introduction……………………………………………………………………………………….1

II – Description of Medical Abortion Methods………………………………………………….1
Summary of three regimens ………………………………………………………………………1
Mifepristone and misoprostol………………………………………………………………………3
Methotrexate and misoprostol…………………………………………………………………….4
Misoprostol only ……………………………………………………………………………………..5

III – Medical Abortion in the Local Context ……………………………………………………..6
Overview…………………………………………………………………………………………………6
Brazil…………………………………………………………………………………………………….8
Colombia………………………………………………………………………………………………..9
Mexico …………………………………………………………………………………………………10
Peru……………………………………………………………………………………………………..11

IV – Advantages and Disadvantages of Each Regimen………………………………………12
Efficacy…………………………………………………………………………………………………12
Cost……………………………………………………………………………………………………..12
Acceptability ………………………………………………………………………………………….13
Feasibility ……………………………………………………………………………………………..13

V – Issues for Choice of Regimens……………………………………………………………….14
Additional Considerations ………………………………………………………………………….15

Appendix 1: Misoprostol and Methotrexate Availability in Project Countries …………….16

Appendix 2: Basics for Medical Abortion Service Delivery …………………………………..18

References………………………………………………………………………………………………20

I – Introduction

It is well understood that unintended pregnancy often results in induced abortion, which, when clandestine, is frequently performed under unsafe conditions. The region of Latin America and the Caribbean (LAC) has one of the highest rates of maternal mortality due to unsafe abortion in the world, accounting for 17% of total regional maternal deaths (WHO, 2004). The consequences of abortion-related mortality and morbidity motivate health and development organizations to invest attention and resources in this devastating public health issue.

In response to this pressing health issue, the International Planned Parenthood Federation’s Western Hemisphere Regional office (IPPF/WHR) is working to expand safe abortion services and prevent unwanted pregnancies throughout the region. As an integral part of the safe abortion regional initiative, IPPF/WHR aims to support the introduction of medical abortion services, a low cost, feasible alternative to surgical abortion. This paper was commissioned to support IPPF/WHR and other organizations’ efforts to identify the best strategies for introducing medical abortion technology and increasing access throughout the region to the fullest extent allowed by the law.

The challenges of providing abortion services in highly restrictive settings such as LAC are numerous. While some exciting gains have been made to liberalize restrictive laws, as in Mexico and Colombia, several countries face active threats to losing existing minimal indications for legal abortion. Nicaragua recently lost already modest indications for legal abortion due to rising political pressure from conservative and religious groups. Basic requirements necessary to provide safe abortion services for legal indications include adequate provider training, essential equipment, medications and supplies. An important obstacle in many countries is provider resistance. The very complex interplay of religious, ethical, professional and personal beliefs combined with fear of community rejection, can be a significant barrier to providing safe services in legal contexts (Faúndes & Barzelatto, 2005).

Such complex issues are beyond the scope of this paper, however. Here, we hope to lay out some of the issues involved in developing a strategy to introduce medical abortion technology to the full extent allowed by the law into reproductive health services in Brazil, Colombia, Mexico and Peru. These are among the most populous countries in the region (PAHO, 2006) and they report some of the highest rates of morbidity and mortality related to unsafe abortion. In the following sections we will summarize information about medical abortion regimens, describe the context and availability of medical abortion drugs in each country, and discuss specific issues relevant to the introduction of medical abortion regimens.

II – Description of Medical Abortion Methods

Summary of three regimens

The use of medications for pregnancy termination, commonly referred to as medical abortion, has grown dramatically over the last two decades. Medical abortion continues to generate research and widespread interest as a safe alternative to surgical procedures due to several advantages. Compared to surgical abortion, medical abortion is a simple, non-invasive procedure that involves the use of pills rather than instruments; it has the potential to be offered by mid-level providers; and women report they enjoy having control over the process and that it feels more natural, similar to a miscarriage. In fact, the effects of the medications used to induce early abortion are similar to those that occur during a spontaneous abortion. Several studies have demonstrated a high rate of satisfaction with the different methods of medical abortion; some of the common advantages and disadvantages reported by women and providers are shown in Table 1 below.

Table 1. Advantages and disadvantages of early abortion methods as cited by women and providers

Medical abortion * Surgical abortion
Advantages • Avoids surgery, anesthesia * • More natural, like menses * • Less painful to some women * • Easier emotionally for some women * • Can be provided by mid-level staff * • Woman can be more in control, involved * • Quicker * • More certain * • Less painful to some women * • Easier emotionally for some women * • Can be provided by mid-level staff * • Provider controlled * • Woman can be less involved

Disadvantages • Bleeding, cramping, nausea (actual or feared) * • Waiting, uncertainty * • Depending on protocol, more or longer clinic visits * • Invasive * • Small risk of uterine or cervical injury * • Risk of infection * • Loss of privacy, autonomy

Table reproduced from Medical Abortion in Developing Countries: An Introductory Guidebook, Gynuity Health Projects 2004

There is less risk associated with properly used modern methods of abortion than with delivery of a live birth (WHO, 2004). In a review of pregnancy-related mortality rates in the United States, Grimes reported that legal abortion claimed fewer lives than carrying a pregnancy to term (Grimes, 2006). Medical abortion regimens are considered to be as safe as surgical abortion and may lead to fewer overall complications, since they do not require the use of surgical instruments or anesthesia. Studies and reports of clinical use of mifepristone medical abortion have shown a good safety profile (Henderson et al, 2005; Hausknecht, 2003). Evidence also suggests a very low rate of infection following the procedure (less than 1%), lower than that reported for both surgical abortion procedures and childbirth (Shannon et al, 2004). Medications used in the most common regimens are safe and are not known to have any effect on future fertility or to increase the risk of abnormalities in future pregnancies.

Since most abortions occur in early pregnancy, usually during the first trimester (Winikoff and Elul, 2006), medical abortion is a particularly good option since it is most efficacious in early gestations(Aubeny et al, 1995). There are three medical abortion regimens that have been widely studied and used in general clinical practice. Table 2 summarizes the primary advantages and disadvantages of each.

Table 2. Advantages and disadvantages of three medical abortion regimens

Regimen Advantages Disadvantages

Mifepristone + misoprostol * • >95% effective * • Acts rapidly * • Medication can be costly * • Not available worldwide

Methothrexate + misoprostol * • >90% effective * • Acts slowly * • Potential to cause fetal malformations

Misoprostol alone * • 85-90% effective * • Least costly * • Widely available * • More side effects * • May be associated with fetal malformations

Table reproduced from Medical Abortion in Developing Countries: An Introductory Guidebook, Gynuity Health Projects, 2004

Misoprostol is a key ingredient in each of the three regimens described below. An inexpensive, synthetic prostaglandin, misoprostol is widely available throughout much of the world, including in the LAC region. It has become the prostaglandin of choice for medical abortion regimens because of its safety, stability at room temperature, and ease of administration. Misoprostol was originally registered for the prevention and treatment of gastric ulcers but has become increasingly recognized as a valuable tool in obstetrics and gynecology due to its effects on the uterus. It is currently registered in five countries1 for ob/gyn indications; these vary by country and include labor induction, intra-uterine fetal death, prevention and treatment of postpartum hemorrhage, and induced abortion either alone or with mifepristone.

The most common side effects of misoprostol include pain and bleeding, effects inherent with the process of abortion, as well as gastrointestinal effects such as nausea, vomiting and diarrhea. These side effects are self-limiting and can usually be easily managed. Severe bleeding that requires treatment can occur, although it is rare (Philip et al, 2004).

Mifepristone and misoprostol

This combination is the gold standard for use in early medical abortion. Mifepristone, an antiprogestin, is licensed and marketed for pregnancy termination in 36 countries; it is also approved for a number of ob/gyn indications and is under study for other potential applications. Mifepristone blocks progesterone receptors so that the uterus can no longer sustain a growing embryo. The drug also increases prostaglandin levels and dilates the cervix, facilitating an abortion (Abuabara & Blum editors, 2004). Adding a synthetic prostaglandin 24-36 hours after mifepristone administration further enhances uterine contractions and expulsion of the products of conception (WHO, 2003). Most women expel the uterine contents within 24 hours of prostaglandin administration but the process may take as long as 2 weeks to complete.

1 Brazil, Egypt, France, Nigeria and Peru.

Mifepristone is manufactured in 200mg pills and is administered orally. In most countries where mifepristone is available, the registered regimen is 600mg of mifepristone followed 36-48 hours later by a prostaglandin, usually 400mcg misoprostol administered orally. Subsequent research has adequately demonstrated that a 200mg dose of mifepristone is as effective as 600mg and is now the standard since it reduces the cost of the regimen with no loss of efficacy (WHO, 2000; Schaff et al, 2000). This regimen can attain more than 90% efficacy for pregnancies through 49 days’ LMP (Shannon et al, 2005).

Other minor adaptations to this regimen have been studied in an effort to achieve greater efficacy in later gestations. Different combinations of routes and doses of misoprostol have demonstrated high levels of efficacy in pregnancies through 63 days’ LMP. Vaginal administration of misoprostol yields high efficacy rates, above 95% (Schaff et al, 2000), in combination with mifepristone and is frequently cited as the regimen of choice, as evidenced by guidelines issued by international and national entities such as RCOG, ACOG and WHO. Until recently, the Planned Parenthood Federation of America used 800mcg vaginal misoprostol in conjunction with mifepristone as their standard regimen for early pregnancies; they recently removed it from their clinical guidelines due to concern about a rare type of bacterial infection thought to be related to vaginal administration. While this link has not proven to have any base in science (Winikoff, 2006), some clinicians are avoiding vaginal use and turning to other routes as a precaution.

In fact, other routes such as sublingual and buccal appear to be good alternatives given evidence to date and may be preferred by some women. Buccal administration of misoprostol in combination with mifepristone has demonstrated good results in pregnancies through 56 days’ LMP (Schaff et al, 2005). The sublingual route has demonstrated high efficacy in gestations up to 63 days’ LMP (Tang et al, 2002). Both routes have a similar pharmacokinetic profile to the vaginal route and consequently have similar side effects, although the sublingual route has more adverse effects at the same 800 mcg dose (Clark et al, 2007(1)). In general, all these variations work quite well and levels of satisfaction do not tend to vary greatly across regimens.

The efficacy of medical abortion is associated with the protocol used and provider experience;success rates increase when women wait longer to expel the products of conception before recourse to surgical evacuation. Use of repeat doses of misoprostol is sometimes used to increase efficacy of the combined regimen, however it has not been systematically shown to improve effectiveness (Clark et al, 2007(1)).

Mifepristone medical abortion is extremely safe; millions of women have safely and successfully used mifepristone regimens for early medical termination of pregnancy. Neither mifepristone nor misoprostol has been associated with long term health effects (Abuabara & Blum, 2004).

Methotrexate and misoprostol

Methotrexate, an anti-metabolite used predominantly for the treatment of cancer, arthritis and psoriasis, has also been proven an effective abortifacient. It can be used successfully in combination with misoprostol and can end early intra-uterine and ectopic pregnancies. Methotrexate acts by stopping rapidly dividing cells from growing, such as those in the embryo. As with mifepristone, adding a prostaglandin such as misoprostol causes the abortion to take place more quickly (Wiebe, 1999; Schaff et al, 1997). While the use of methotrexate as an abortifacient has been well documented as safe and effective, it has not yet been registered in any country.

Methotrexate and misoprostol is most used for very early pregnancies up to 56 days’ LMP, and there is evidence for success through 9 weeks’ amenorrhea. The most commonly used regimen is 50 mg methotrexate ingested orally, followed 5-7 days later by 800 mcg vaginal misoprostol. Evidence suggests that a repeat dose of misoprostol 24-48 hours later may increase effectiveness. The overall success rate of methotrexate-misoprostol medical abortion reported in the clinical trial literature varies between 82-95% (Clark et al, 2007(1)).

Methotrexate is available as both a solution and oral tablets. The solution can either be ingested orally or injected intramuscularly. Researchers have found that regimens administering the misoprostol on day 4, 5, or 6 each work equally well (Carbonell et al, 1998).

Pharmacokinetic studies demonstrate that the typical 50 mg oral dose of methotrexate is safe, since blood serum levels do not reach sustained toxic levels. However, women should be informed about the potential teratogenicity of methotrexate and misoprostol and counseled regarding the importance of surgical completion if the drugs do not successfully end the pregnancy. (Abuabara & Blum, 2004).

The side effect profile of methotrexate-misoprostol medical abortion is similar to that of mifepristone-misoprostol regimens. A study comparing the side-effects of mifepristone and methotrexate regimens found that headaches were appreciably more common after mifepristone and that diarrhea, fever, chills, and “worst” pain score reported by women were significantly more common after methotrexate (Wiebe et al, 2002). Although rare, hemorrhage requiring treatment can occur (Philip et al, 2004). Management of side effects is similar to mifepristone regimens.

Although success rates of this method are similar to those achieved with mifepristone, abortion with methotrexate requires more time to complete. Expulsion usually will occur with time, on average 22
to 29 days after methotrexate administration, and sometimes after longer periods, between 29 and 45 days.

The WHO does not recommend methotrexate due to the potential for teratogenic effects for ongoing pregnancies. However, it can achieve high success rates and is the method of choice in some countries where mifepristone is not approved, including Canada, due to its generally superior efficacy compared to misoprostol alone (Aldrich & Winikoff, 2007).

Misoprostol only

Misoprostol has been invaluable in the development of non-surgical abortion. As described previously it is a critical component in all commonly used regimens, and is widely used both as a stand-alone method and in combination with other medications. Misoprostol emerged as a preferable alternative to other synthetic prostaglandins which caused more severe side effects and because it is orally active, thermostable, less expensive, and widely available by comparison. There is more than a decade of published experience on the use of misoprostol alone for induced abortion in the first and second-trimesters, and in many parts of the world misoprostol alone is already the standard of care for induced abortion in the second trimester.

Misoprostol alone for pregnancy termination is between 85-90% effective among women up to 9 weeks amenorrhea, decreasing to 80-90% between 10 and 12 weeks. Through 63 days’ gestation an 800mcg dose of vaginal misoprostol repeated at 24-hour intervals is the most frequently tested regimen and is recommended by the World Health Organization (WHO 2004); it has also been recommended by a group of experts (Philip et al, 2004). Studies indicate that there is little gain in effectiveness with a second dose (Clark et al(1), 2007), although some practitioners may prefer to give a third dose at follow-up if the abortion is incomplete. As with other regimens, the medication can be administered either in the clinic or at home.

Bleeding patterns and complications are similar for misoprostol alone regimens and combined therapy with either methotrexate or mifepristone. Vaginal bleeding usually begins within the first 24 hours of administering misoprostol and lasts between 7 to 14 days on average, and spotting through the next menstrual period is common (Clark et al, 2007(1)). Cramping usually precedes or begins simultaneously with bleeding, and can begin as soon as 30 minutes after misoprostol administration (Say et al, 2005). Hemorrhage requiring treatment is rare but can occur (Philip et al, 2004).

Most recommendations indicate vaginal administration of misoprostol as the preferred route due to greater efficacy compared to oral misoprostol through 63 days’ LMP, however buccal and sublingual routes of misoprostol show promise as an alternative to the vaginal route when used with mifepristone and may prove alternatives to vaginal misoprostol alone. In addition, non-vaginal routes may be preferred by some women and will decrease the possibility of discovery of the tablets if the abortion is clandestine. Evidence suggests that sublingual misoprostol may be similarly effective through 9 weeks amenorrhea, and potentially can be given at a lower dose. Buccal misoprostol in conjunction with mifepristone has become used with greater frequency, particularly by clinicians in the U.S., however no systematic research has been done on misoprostol alone and only anecdotal information exists to support a buccal misoprostol alone regimen (Clark et al, 2007(1)).

Common adverse effects following misoprostol administration are widely documented and include chills, fever, nausea, vomiting, and diarrhea. As with other regimens most of these side effects can be easily managed. Studies have shown that the adverse effects following oral, vaginal, buccal and sublingual regimens are tolerable and that the method is highly acceptable.

III – Medical Abortion in the Local Context

2 In April 2007, the Mexico City Legislature approved a bill that would allow women to obtain a legal abortion during the first twelve weeks of pregnancy in the Federal District; similarly, in Colombia, recent changes to liberalize abortion laws occurred in 2006. Therefore, it is uncertain the potential impact of the new legal status on access to services.

Overview

In Brazil and Peru2, abortion laws are fairly conservative and access to legal abortion services is limited predominantly due to lack of clear guidelines on how to obtain legal services, provider resistance, inadequate provider training and/or lack of necessary supplies and equipment. Nonetheless, viable medical abortion options do exist. In order to understand the local context, research and interviews were conducted with key informants in each country. Two dozen individuals including physicians, nurses, researchers, pharmaceutical industry representatives, and women’s health and rights advocates provided information about medication distribution, cost and accessibility. This research yielded the following information about each project country, which will inform a strategy for the introduction of safe and legal medical abortion services.

Misoprostol is registered for gastrointestinal indications in all countries and is also registered for ob/gyn use in Brazil and Peru3. In the four project countries, misoprostol is widely available through both formal and informal channels. In all the countries except Mexico, there are local pharmaceutical companies that produce generic misoprostol and in some, local distributors import international products. In all the countries, local pharmacies often sell misoprostol without a prescription, even though it is technically a prescription drug. In Brazil, misoprostol sales are more tightly controlled and the medication can be purchased only through hospitals.

The major concern regarding black market misoprostol is the lack of reliable quality, including whether the substance really is the drug at all. In some countries falsified sugar or flour pills are common, and there are reports of other drugs sold to women that cause vaginal bleeding but are not abortifacients. Sellers, including pharmacists selling registered pharmaceuticals, often fail to counsel their clients on appropriate dosages and routes of administration for abortion induction with misoprostol.

The price of misoprostol varies greatly depending on the country. Women are usually sold individual pills, but sometimes they can purchase an entire bottle (usually containing 28 pills). The prices through these channels range from US$1 to $30 per pill. Where pills are more expensive, a self-induced misoprostol abortion can be quite costly in the context of the average monthly salary in the region, approximately $100-$200. In countries where the price of misoprostol has become inflated due to clandestine use or because of increased restrictions on sales, physicians with private clinics may rely on the clandestine local market or obtain misoprostol in neighboring countries where the pills are less expensive.

Methotrexate is largely available in the four countries, although its distribution is restricted to hospital use since it is indicated primarily for cancer treatment. It is sometimes used to treat ectopic pregnancies. In contrast, mifepristone is not available in any of the countries.

Legal indications for abortion, drug availability and distribution channels, and guidelines for use of medical abortion are described for each country in the following section. A table of medications available in each country can be found in Appendix 1.

3 The Brazilian manufacturer of misoprostol, Hebron, has registered the drug for the following ob/gyn indications: labor induction, intra-uterine fetal death, and legal abortion. Information obtained by Hebron staff indicates that efforts are under way to register misoprostol in Mexico and other LAC countries.

Brazil

Abortion is legal in Brazil for two primary indications – if the pregnancy poses a threat to the woman’s life, or if it is the result of rape or incest. A third indication is allowed in cases of fetal malformations incompatible with life outside the womb. Only high-level hospitals are allowed to provide legal abortion services in Brazil, and they are limited to about 60 throughout the country. Lower-level health facilities such as clinics are not approved to perform abortion services.

Misoprostol became available in Brazil in 1984 when it was approved for gastric ulcer prevention and treatment; it was widely available in pharmacies for many years and used popularly by women to induce abortion. In 1998, regulations involving the sale and distribution of misoprostol were tightened, permitting only hospitals with specific government approval to purchase it and prohibiting its advertisement. These regulations are determined by ANVISA, the Brazilian drug regulatory agency. Today, misoprostol is produced domestically by Hebron Pharmaceuticals under the name of Prostokos, and is registered for three ob/gyn indications – labor induction, intra-uterine fetal death, and induced abortion. Prostokos comes in three doses and is formulated for vaginal administration4. While Prostokos is currently authorized for hospital sale and use only, it is predominantly used for labor induction and intra-uterine fetal death, as legal abortion is rarely performed. However, hospitals must be very diligent to obtain a purchasing license as the process is complicated and time consuming, representing a significant barrier to service delivery.

The Ministry of Health published technical guidelines for legal abortion in 20055, which highlight medical abortion using misoprostol alone regimens as one of three approved options for first trimester abortions and the preferred method for second trimester abortions. In the same year, guidelines for treating victims of sexual violence were published with similar recommendations for medical abortion6. In both guidelines, misoprostol is also recommended for cervical maturation prior to surgical abortion.

Given the lack of services in Brazil, many women seek out misoprostol on the black market, which flourishes in big cities and in the border regions. Venues that sell misoprostol include select pharmacies, traveling salesmen, and the internet. Borders with Peru, Colombia, and Paraguay are often hot spots for this trade, as these areas are not highly patrolled, particularly along waterways. Traditional healers and midwives (“parteiras”) sometimes give women misoprostol, as do clandestine abortion providers. The cost of misoprostol through these routes varies significantly by region. For example, in the northeastern state of Pernambuco, women can pay US$10-12 per 200mcg pill, whereas in São Paulo, individual pills tend to be more expensive and range from $20-30 per pill. Prostokos products cost approximately $5-9 per 200mcg pill and $2 per 25mcg pill.

4 A Hebron representative indicated that a 200mcg pill formulated for sublingual use is under development for prevention and/or treatment of postpartum hemorrhage.
5 Norma Técnica: Atencão Humanizada ao Abortamento: http://portal.saude.gov.br/portal/arquivos/pdf/Atenção Humanizada.pdf. pgs 25-7.
6 Norma Técnica: Prevenção e Tratamento dos Agravos Resultantes da Violencia Sexual contra as Mulheres e Adolescentes: http://portal.saude.gov.br/portal/arquivos/pdf/norma prevenção atualizada.pdf. pgs 48-9.

At least two national methotrexate products are available for direct distribution to hospitals. Methotrexate is used primarily for cancer treatment and some ob/gyn indications. It comes in both pill and injectable formulations; prices are noted in Appendix 1.

Colombia

For almost thirty-five years, Colombia was one of only three countries in the LAC region that had no single indication for legal abortion, not even for women for whom carrying a pregnancy to term would jeopardize her life or severely compromise her health (González-Velez, 2005). In May 2006, after significant lobbying and pressure from local and international women’s health advocates, Colombia’s courts eased restrictions, and abortion is now legal for three indications – if the pregnancy poses a threat to the woman’s life, if the pregnancy is the result of rape or incest, or in cases of non-viable fetal malformation7.

After the change in law, a guide for legal abortion indications was developed by the Ministry of Social Protection (MSP). The Colombian technical guide was adapted from the WHO document published in 2003, Safe Abortion: Technical and Policy Guidance for Health Systems. The guide was published in December 2006 and suggests methods for pregnancy termination according to gestational age. The guide includes the use of misoprostol alone or a combination of mifepristone followed by a prostaglandin such as misoprostol, up to 12 weeks of gestation. For gestations greater than 12 weeks, the guide suggests the use of mifepristone followed by repeat doses of a prostaglandin such as misoprostol or gemeprost, and dilation and aspiration.

As with most countries, misoprostol is registered in Colombia for gastrointestinal indications. MOH regulations have always required that misoprostol be sold with a medical prescription; however, pharmacies only rarely obeyed this regulation. When it was discovered that the pills were being used for abortion the MSP created regulations similar to the ones that exist in Brazil for its sale and distribution. However, since May 2006, MSP no longer considers misoprostol a special control drug, and it is regulated by the same norms that regulate most other drugs. Two national companies produce misoprostol and one international product, Cytotec, is sold by Pfizer. All come in 200mcg tablets, and the cost ranges from US$0.75-2.20/pill.

Pharmacists now rely on the black market to buy Cytotec, which is the product that women get when they buy the pills in the pharmacy. Pharmacists usually sell 4 or more pills; the cost of individual pills is about $5. The recommendation is often that they be administered 2 orally and 2 vaginally.

Methotrexate is also available for hospital use only and is used for treatment of cancer, psoriasis, arthritis and ectopic pregnancy. The cost ranges from $0.16 per 2.5mg tablet to $4.25 per 50mg/ml ampoule.

7 Sentencia C-355 May 10, 2006

Mexico

In April 2007, the Mexico City Legislature approved a bill that would allow women to obtain a legal abortion during the first twelve weeks of pregnancy; the bill has since passed into law allowing for abortion services in the Federal District. However, at the state level, Mexico’s law varies. Only pregnancies resulting from rape can be aborted in all 32 states. Twenty-nine states allow abortion if pregnancy poses a threat to the woman’s life. Some states also permit abortion for fetal malformations, if the pregnancy is the result of forced artificial insemination and for economic reasons when the woman has at least three children8.

Misoprostol is sold by Pfizer, and is easily available through pharmacies without a prescription (Lara et al, 2006) as well as on the black market. It can often be found in herbal markets, through the internet, and around university campuses. The pharmacy and black market price of the drug has increased significantly in the last few years and can range from US$3-5/pill. The drug is registered for gastrointestinal indications, but the Secretary of Health has acknowledged the use of misoprostol for the prevention and treatment of postpartum hemorrhage in a publication released in 20029.

National guidelines were produced by the National Center for Gender Equity and Reproductive Health in 2004 outlining medical care and methods for legal pregnancy termination for the treatment of rape survivors10. Among the recommendations for 1st and 2nd trimester pregnancy termination is the use of misoprostol alone; specific regimens vary according to gestational age. Although abortion is legal for at least one indication in each state and all federal and public hospitals are required to perform legal abortions, a lack of state-level guidelines for abortion service provision limits accessibility to services; to date only two states11 and the Federal District have developed guidelines.

Some organizations such as Ipas and ESAR have worked to train pharmacists in Mexico to inform them about proper dosing, timing, and routes of administration of misoprostol for pregnancy termination. However, anecdotal information is that regimens used by women to induce abortion vary greatly. In cases of incomplete abortion women may opt to use clandestine services if she has the financial resources; alternatively women go to public hospitals to complete the abortion.

Methotrexate is registered for cancer treatment and available predominantly in hospital settings; its use for induced abortion is not widely known, however it appears to be low due to its limited availability outside of hospitals. No information was obtained on cost.

8 GIRE: www.gire.org.mx
9 Secretaría de Salud, Dirección General de Salud Reproductiva. D.F. México. Prevención, Diagnóstico y Manejo de la Hemorragia Obstétrica, Lineamiento Técnico, 2002; pgs 41-43: http://www.generoysaludreproductiva.gob.mx/IMG/pdf/HEMORRAGIAOBSTETRICA.pdf
10 Centro Nacional de Equidad de Género y Salud Reproductiva, D.F. México. Atención Médica a Personas Violadas, 2004; pg 37: http://www.generoysaludreproductiva.gob.mx/IMG/pdf/guiaperv.pdf
11 Baja California, Baja California Sur

Peru

Since 1924, abortion is legal in Peru only in two circumstances – when pregnancy poses a threat to the woman’s life, and when the pregnancy may cause permanent damage to the woman’s health. To date, there are no national protocols for abortion, however three relatively new sets of guidelines have been developed in high-level hospitals that will serve to standardize services. Prior to their development, health care providers sought technical guidance of the national ob/gyn society (Sociedad Peruana de Obstetricia y Ginecología – SPOG) or of colleagues in other countries such as ESAR.

The most recent guidelines developed in February 2007 at the Maternidad de Lima12, a specialized maternity hospital that often serves as a national reference, list the medical indications for which abortion is legal and the necessary infrastructure and professional requirements to perform an abortion. Under these guidelines, an ob/gyn specialist must perform an abortion and hospitals must have wards with obstetric and neonatal intensive care units (designated as level IV hospitals in Peru). Under the guidelines, misoprostol is recommended among the options for termination of first and second trimester pregnancies.

A second set of guidelines for legal abortion was developed by Belen Hospital13. These guidelines, written by Promsex, a prominent women’s health NGO in collaboration with SPOG, explain in greater detail technical procedures for performing abortions, and include misoprostol alone regimens for first and second trimester abortion. A national teaching hospital, Hospital Nacional Docente Madre Niño San Bartolomé, approved guidelines for therapeutic abortion in 2006.

Several misoprostol products are available in Peru. Misoprostol is registered for gastrointestinal indication but the product is not yet commercialized for the same ob/gyn indications for which the Brazilian Prostokos product is registered. The MOH sells misoprostol through its pharmacies in health institutions by prescription only but can also be found through informal channels. The price per 200 mcg pill ranges from US$0.79 – $2.10.

Even when a woman’s life is at risk and legal abortion is approved, it rarely occurs. In general, there has been a decrease of infections due to induced abortion, and some believe this is due to the use of misoprostol. It is not known how women obtain information about the dosage and route for misoprostol self-induction but anecdotal information suggests that women are using it vaginally. Officially, if a woman is suspected of having induced an abortion, staff are required to send her to the emergency department for evaluation, interview the woman to determine how the abortion was induced, and inform the police about the illegal procedure; however, this last step is rarely taken and the woman is usually hospitalized, treated, and the case is filed as a hemorrhage or spontaneous abortion.

According to one source there are numerous methotrexate products on the market, both national and international; they are summarized in Appendix 1 along with available misoprostol products.

12 Instituto Nacional Materno Perinatal, Maternidad de Lima. Aborto Terapéutico, 2007
13 Promsex, SPOG. Departamento de Gineco-obstetrícia del Hospital Belén de Trujillo: Protocolo de Manejo de Casos para la Interrupción Legal del Embarazo, 2006

IV – Advantages and Disadvantages of Each Regimen

Efficacy

A combined regimen of mifepristone and misoprostol for early pregnancies is considered by many experts to be the gold standard due to the regimen’s high efficacy and safety profile (WHO, 2004). Where mifepristone is not available, methotrexate used in conjunction with misoprostol is the second most efficacious medical abortion regimen and tends to produce higher rates of success than misoprostol alone (NAF, 2005; Clark et al, 2007(1); Aldrich & Winikoff, 2007). However, studies of misoprostol alone have also achieved acceptable efficacy rates and should be considered a good option depending on the local context and other factors such as cost, acceptability and feasibility, addressed below.

Cost

Some of the costs related to providing medical abortion services overlap with those for surgical procedures, such as lab costs, ultrasound, analgesics and staff time. However, since medical abortion involves the administration of pills and instruments and anesthesia are not required, the overall costs can decrease significantly. The relatively low cost of the medications makes medical abortion a feasible option. Planned Parenthood Federation of America (PPFA) analyzed data from member affiliates to evaluate costs involved in providing mifepristone medical abortion and 1st trimester aspiration abortion at three different affiliates. When looking only at staff time, overall, medical abortion required about half the staff time compared to surgical abortion. It is therefore possible to attend to more women who opt for medical abortion than surgical, thereby increasing the potential to reach more women (Fjerstad, 2005).

While more information about the precise cost of methotrexate in each country is not available, preliminary information indicates reasonably inexpensive prices. There appears to be local distributors in every country. In addition, given that the drug is used solely in hospitals14 in most countries and therefore less likely to be affected to wild fluctuations in cost as can occur with black market pharmaceuticals, it is likely that the price of the drug would not be an inhibiting factor for its use.

For misoprostol-alone regimens, only eight to twelve 200mcg pills are usually required for gestations through 9 weeks’ LMP. Given the relatively inexpensive cost of misoprostol in most of the project countries, it seems quite feasible to employ this regimen. Even in countries where misoprostol has undergone major price increases recently, as in Mexico, the small number of pills needed per person
makes it still relatively inexpensive compared to the costs involved in providing surgical procedures.

Although mifepristone is not currently available in any of the project countries, it should not be discarded as a potential option. While mifepristone tends to cost more than misoprostol and methotrexate, there are low-cost mifepristone products produced in India and China (approximately $5-10/pill) that likely would not greatly affect the overall cost of the regimen if they were to be imported. Mifepristone-misoprostol regimens use fewer misoprostol pills than regimens based on misoprostol-alone, thus offsetting some of the additional cost of the mifepristone. In fact, when one considers the high efficacy of mifepristone-misoprostol regimens, the added cost of the drug itself may be less than the additional costs incurred for less effective medical abortion regimens that result in extra surgical procedures. However, in countries where demand for any medication is expected to be low, as is the case for abortion drugs in highly restrictive legal settings, pharmaceutical companies are not eager to incur expensive registration costs for drugs with abortion induction as their only approved indication.

14 Although methotrexate is used predominantly in hospital settings because of the conditions it treats, the drug is not
restricted to hospital use only.

Acceptability

There is not great variation in acceptability among medical abortion regimens. Although methotrexate regimens usually require more time to complete the abortion process, several studies show a high level of acceptability to women (Clark et al, 2007(1); Wiebe et al, 2006). As with mifepristone-misoprostol or misoprostol-alone, even among women for whom the method failed, a high percent have reported they would choose medical abortion again for a future abortion, and/or would recommend the method to a friend or family member.

Women who administer misoprostol alone regimens may experience more fever and chills, compared to the combined therapy with mifepristone and misoprostol which tends to produce more nausea and vomiting. However, most adverse effects for all three regimens are transient, last less than 24 hours, and do not require treatment beyond short term use of anti-diarrheal, anti-nausea or fever-reducing medications. (Clark et al, 2007(1))

The administration of misoprostol in the woman’s home is an aspect of medical abortion service provision that has an impact both on acceptability and cost, as it eliminates visits to a health center. Women who administer misoprostol at home appreciate that they are able to experience the abortion in private, allowing them to choose whether and whom to have as support persons during the process. Home administration also reduces the time and expenses involved in a return visit to the clinic, both for the woman and providers.

Since methotrexate abortions take longer to complete than mifepristone and misoprostol alone regimens, some women may ultimately decide not to wait until the process is completed and request a surgical intervention to complete the abortion. This may have some impact on their overall satisfaction and also has implications for cost related to increased numbers of surgical interventions.

Feasibility

Medical abortion has been hailed as an easy to use, low-tech option, making it particularly feasible for use in low-resource settings and lower-level health facilities. First, since it does not involve the use of instruments or anesthesia, it can be provided by mid-level health care providers such as nurses. Moreover, non-clinicians such as counselors can play an instrumental role in educating women about medical abortion regimens and expected side effects and help women make informed decisions about available options. In addition, most of the side effects associated with medical abortion regimens are anticipated and easy to manage. In the health facility, mid-level staff (such as counselors, nurses, midwifes, or a trained support person) should be able to handle most problems. In rare cases, a physician may be required to manage rare, severe side effects.

While ultrasound is consistently used in many countries for gestational dating and/or to confirm that the abortion is complete (most common in developed country settings that have the resources), it is not an absolute requirement. Investigators are exploring ways to further simplify medical abortion regimens, and there is some evidence to date that this can be achieved by reducing reliance on ultrasound and possibly eliminating the follow-up visit, among others (Clark et al, 2007(2), Clark et al, 2007(3)).

While equipment and supplies needed to treat incomplete abortions and ongoing pregnancies are not absolutely necessary on site, it is indispensable to have an established referral system in place, should ultrasound and/or surgical completion be required. For a list of basic requirements for medical abortion service delivery, see Appendix 2.

V – Issues for Choice of Regimens

All regimens described previously work quite well and there are many factors that influence choice including drug availability, cost, service delivery feasibility, women’s preferences, and issues relevant to the local context. For example, misoprostol as a common component to all regimens makes it indispensable to medical abortion service provision. The option of home use of misoprostol is also common among all regimens which impacts cost of service provision and acceptability to women. Access to drugs may have the biggest impact on regimen choice. The following table summarizes these key issues for each medical abortion regimen.

Table 3. Issues for choice of regimens

Issue * Choices * Considerations
Regimen? * • Mifepristone + misoprostol * • Methotrexate + misoprostol * • Misoprostol-alone * • Availability/ access to medications * • Cost * • Efficacy * • Safety * • Acceptability
Route and dose of misoprostol? * • Oral, vaginal, sublingual, buccal * • 400mcg, 600mcg, 800mcg * • Repeat doses * • Each route has similar side effect profile, with minor variations; generally all tolerable * • Vaginal route may not be favorable if used in clandestine settings * • Buccal & sublingual may be preferred by women * • Choice depends in part on gestational age * • Repeat doses of misoprostol may (?) improve success rates
Who is eligible? * • Gestations up to 49, 56, 63 days’ LMP * • Later gestations * • Contraindications * • All regimens work best at earlier gestations, however there is evidence showing efficacy in later first trimester * • Long lists of contraindications seem unnecessary
Where to take drugs? * • Home * • Clinic * • Choice for women? * • Safety * • Cost * • Feasibility
Who can provide services? * • Obstetrician * • Any physician * • Nurse/ midwife * • Mid-level providers can safely provide services
Where in the health system? * • Hospital * • Clinic * • Private practice * • Referral to higher level of care for surgical back up or ultrasound if not available in clinics or private practice

Additional Considerations

Introduction of New Methods into Reproductive Health Services
Health centers that do not currently provide abortion services can provide medical abortion services, as long as they have a reliable referral system to manage potential complications and failures. Since mifepristone became available in the US in 2000, PPFA successfully introduced medical abortion services into 75 member affiliates that did not previously offer any abortion services (Fjerstad, 2005). Among the noted advantages are the expansion of services, and the normalization of abortion care in the context of well-woman services. WHO also suggests that medical abortion can be introduced into health-care settings that do not already provide abortion services (WHO, 2006).

Off-label Use

The only drug that is registered for abortion induction of the three regimens discussed is mifepristone; methotrexate and misoprostol are both used for this indication as off-label drugs. Misoprostol is an exception to other innovations in ob/gyn that become rapidly integrated into medical practice. While it is often found to be in the pockets of obstetricians and gynecologists in countries in which it is available, it has rarely been approved for ob/gyn indications.

Off-label use of medications is quite common and widely accepted in the medical profession. The US Food and Drug Administration supports the practice stating that “Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects (USFDA, 1998).”

Many countries do not have specific regulations dealing with medical abortion since it is a relatively new technology. However, each country may have practices and/or recommendations on use of available drugs for purposes other than those approved; these should be known by health care providers to inform local practice.

Appendix 1: Misoprostol and Methotrexate Availability in Project Countries

Drug * Product * Lab/Origin * Presentation * Cost US$ * Notes
BRAZIL
Misoprostol * Prostokos * Hebron / Brazil * Tablets: 25μg (100 per pk) 100μg (not on market) 200μg (50 per pk) * $211 n/a $464 * Cytotec and other products available on the black market and internet;
range from $20 – $30 per pill
Methotrexate Metrotrex Miantrex * n/a Pfizer * Tablets: 2.5 mg (pk of 20 pills) Injectables: 50mg 500mg 1g * $8 $10 $60 $144 * Prices vary by laboratory; average costs are noted

COLOMBIA
Misoprostol Cytotec * Pfizer/ England, Colombia * Tablets 200μg / 28-pill bottle * $2.20 /pill (Colombia) * Black market ranges from $5- $20/pill
Cytil * Tecnoquimicas/Colombia * Tablets 200μg / 28-pill bottle
$1.20/pill
Misoprol Quimicol/ Colombia Tablets 200μg / 28-pill bottle * $0.75/pill *
Methotrexate Emtexate * PCP Pharmacheme imported to Colombia by Alpharma/Netherlands * Injectable 50mg/ml Tablets 2.5mg/30 or 100 per pk * $4.25 each $0.16/tablet

MEXICO
Misoprostol * Artrene SR (misoprostol + diclofenaco Na) * Merck * Tablets Diclofenaco Na 100 or 150 mg + 100 μg misoprostol/ 10 or 20 per pk * n/a * Registered for arthritic conditions but suspected use as abortifacient
Cytotec * Pfizer / England & Mexico * Tablets 200 μg / 28-pill bottle * $80-150 * Estimated sales of 200,000 bottles/year
Cytil * Tecnoquimicas/Colombia * Tablets 200 μg / 28-pill bottle * $50 * Black market from Colombia
Methotrexate * Ledertrexate *Oxatem *Emthexate *Trixilem®RU 15 * Wyeth SA Laboratorios Best Lemery S. A. * *Tablets 2.5 mg/ 100 per pk *Tablets 2.5 mg *Tablets 10 mg; Injectables: 2.5, 5, 25,100mg/ml *Injectables: 50 mg/2ml; 500 mg/20 ml; 1000mg/40 ml * n/a

15 http://www.facmed.unam.mx/bmnd/plm2k6/prods/36367.htm

PERU
Misoprostol Cytotec * *Pfizer/England and Mexico * Tablets 200μg /28-pill bottle * $59-150/ 28- pill bottle
Cytofine * Master Farma/ Peru Induquimica S. A./Peru * Tablets 200 μg 12, 28, 40, 100, 4-pill pk * $22-59/ 28-pill bottle
Misoprolen * n/a * Tablets 200 μg / 28-pill bottle * $22-59/ 28- pill bottle
Prostokos * Hebron/ Brasil * Pastillas:25μg (100 per pk) 100μg 200μg (50 per pk) * Not yet on the market
Methotrexate † * Metrotrexato * * Induquimica/Peru * Medifarma /Peru * Meditab Specialties Pvt.Ltd./India * Monte Verde / Argentina *Ebewe Pharma / Austria * IMA S.A.I.C. /Argentina *Korea United Pharm Inc. /South Korea *Pfizer (Perth) PTY Limited-Australia * Laboratorios FILAXIS/ Argentina * * Tablets: 2.5mg (pks of 25, 30, 50, 100) * Injectables: 50mg/2ml 500mg/20ml 1000mg/10ml * $5-36 n/a
Reumatrex * Lab AC Farma S. A/Peru * Injectables 500 mg * $88
Meticil * *IVAX/ Argentina *S.A./Argentina * Tablets: 2.5 mg 20, 50, and 100 pill pk Injectable: 548.37 mg/ vial * $27 for 20- pill/pk
Merex * *Intas *Pharmaceuticals Ltd. /India * Injectable 50 mg * $5 *$32
Mitrul * Monte Verde S.A./Argentina * Tablets: 2.5, 7.5, 10mg (packs of 10, 20 ,30, 50, 60, 90 y 100) * n/a
MTX * Choongwae Pharma Corporation /South Korea * 50 mg/2 ml vial 6, 8, 12, 20, or 25 vial/pk * n/a
Neometho * Laboratorio Boryung Pharmaceutical Co Ltd Korea * Injectable: 25mg/ 2ml * n/a
Tratoben * Pisa S.A. D E C.V./Mexico * 50 mg/vial (1, 25, 50, 100 vials) * n/a
Trixilem * Lemery S.A. De C.V. /Mexico * 2.5 mg/tablet, 50 tablets Injectable: 50mg Injectable: 500 mg * $25 $19.50 each $49 each
Zexate * Dabur Pharma Limited /India * 2 ml vial, 50 mg * n/a

† Local sources reported an unusually large number of products.

Appendix 2: Basics for Medical Abortion Service Delivery16

The basic requirements for medical abortion service delivery include trained staff and the required medications. Staff should include professionals able to determine eligibility, confirm success, provide women with and/or refer them to emergency back-up care.

A. Staff training – Staff at facilities offering medical abortion should be trained in each of the following:

Introduction of risk-reduction model.

Protocols for medical abortion: Staff should be knowledgeable about each medication and the protocol being used in the clinic.

Information provision: Staff should receive comprehensive training on counseling for medical abortion.

Dating gestational age: Staff should be able to assess gestational duration by review of pertinent history, symptoms, and physical exam. Since the effectiveness of medical abortion does not decrease dramatically with each day of increasing gestational length, it may not be necessary to date gestational age precisely. Ultrasonography may aid in determining gestational age but is not a requirement for service provision.

Identifying rare pregnancy abnormalities: Staff should be knowledgeable about warning signs for rare pregnancy abnormalities such as ectopic pregnancies and hydatiform mole. Since women presenting for medical abortion usually come early in their pregnancies, providers have an opportunity to diagnose rare conditions early. Mifepristone and misoprostol have no effect on ectopic and molar pregnancies.

Determining success: Abortion status can be assessed at follow-up by clinical history and exam. For example, if the clinician is able to detect increase in uterine size compatible with additional weeks of fetal growth or if the woman is having prolonged bleeding problems, additional intervention may be needed. Ultrasonography may aid in determining whether the abortion process is complete but is not required for service provision.

Values clarification: Discussion with staff about values may be useful, especially in instances where some of the staff is ambivalent about providing abortion services.

B. Medications

Abortion Medications: All medications can be administered either at home or in the clinic. Regardless of where the drugs are administered, women should be carefully counseled on how and when to take each drug and on potential complications, probable side effects, and management of these occurrences.

16 Adapted from Providing Medical Abortion in Developing Countries: An Introductory Guidebook, Gynuity Health Projects, 2004.

Pain medications/anti-emetics: These products can be given to women in advance to be used as needed to help to ease side effects.

C. Emergency care facilities/referral services

Surgica termination: Since the method is not 100% effective, medical abortion providers should be able to perform or refer women for surgical completion, when needed.

Emergency care: Women need to know where to go for emergency care. Most back-up care is similar to that needed by women following spontaneous abortion, and many communities have a health care facility already in place to provide such care.

D. Desirable (but not required) facilities

Waiting area: If misoprostol is taken at the clinic, it is convenient to have an area where women can wait after taking the medication. A sufficient number of toilets should be nearby. Beds are rarely necessary, but comfortable chairs can be useful. Ideally, clinics provide space for a woman’s companion to stay with her during the abortion process.

Ultrasonography: Ultrasonography can be useful in determining gestational age, identifying pregnancy complications, and confirming abortion completion when used by highly skilled providers. However, when overused, ultrasound can be associated with missed diagnoses, erroneously dated pregnancies, and a high rate of unnecessary surgical completions. A low-sensitivity urine pregnancy test may be a potential alternative to confirm the success of the treatment, although further research is required.

Ant -D globul n: If the local standard of care indicates anti-D globulin for women undergoing surgical or spontaneous abortion, this care should be provided with medical abortion until further evidence becomes available.

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