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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Objectives  To study the efficacy and acceptability of a simplified medical abortion regimen in Vietnam.

Design  Open-label study.

Setting  One peri-urban and three urban hospitals and four urban maternal–child health family planning clinics located in Northern, Central and Southern Vietnam.

Sample  A total of 1601 women seeking abortion services from January 2001 to December 2001.

Methods  Consenting women presenting for abortion services with gestations less than 56 days LMP who met the inclusion criteria were given 200 mg mifepristone and offered the choice of either home or clinic administration of 400 μg oral misoprostol two days later.

Main outcome measure  Complete abortion rate of 89.2% (n= 1395), with 1.5% (n= 24) of the women lost to follow up. The majority of women (>90%) reported that their medical abortion experience was either ‘very satisfactory’ or ‘satisfactory’.

Results  There was a strong preference for home administration of misoprostol, with more than four-fifths of the study population selecting to administer the prostaglandin at home. Location of misoprostol administration did not affect efficacy rate. Regardless of location selected, women expressed a high degree of satisfaction with the medical abortion experience.

Conclusions  Medical abortion with the option of home administration of misoprostol is safe and feasible for introduction into the Vietnamese healthcare system.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Mifepristone medical abortion has been available and widely used throughout Europe and China for well over a decade. In recent years, this modern abortion method was also approved for use in North America (the United States), Asia (India and Vietnam) and Africa (South Africa and Tunisia). This article reports on a clinical study conducted in eight healthcare facilities across Vietnam to provide the data requested by the Vietnamese Ministry of Health for formal approval and introduction of mifepristone medical abortion throughout the country.

Abortion remains a widely practised method of birth control in Vietnam, with a reported rate of 100.1 abortions per every 1000 women of reproductive age.1 Medical abortion has been available to Vietnamese women via clinical studies conducted by the World Health Organisation and the Population Council since 1992.2–5 These previous studies have demonstrated the safety and efficacy of this abortion method. While researchers have tested and continue to test a range of clinical regimens internationally, an overview of the available data from Vietnam suggests that regardless of the mifepristone dose (200 mg vs 600 mg), the number of clinic visits required (two, three or more) or the location of misoprostol administration (home, clinic or, in rare instances, elsewhere), mifepristone–misoprostol medical abortion is a highly effective and widely acceptable means of early pregnancy termination for women in this country.2–5 Research in a range of settings, including the United States, Tunisia and Guadeloupe, has shown that medical abortion regimens with reduced (200 mg) mifepristone doses and home administration of misoprostol are also safe, highly effective and widely acceptable.6–8

The present study expanded upon earlier Population Council research offering a simplified regimen of medical abortion to women seeking early abortion at Hung Vuong Hospital.5 In the initial study, 93% of women successfully completed their abortion using a simplified regimen consisting of 200 mg of mifepristone followed by 400 μg of oral misoprostol, either at home or at the clinic. These promising results provided strong evidence of the efficacy and acceptability of this simplified medical abortion regimen, but did not address widespread use at different levels of healthcare services throughout the country.

Given the Ministry of Health's interest in introducing medical abortion within the national healthcare system, the Population Council teamed with the Maternal Child Health/Family Planning branch of the Ministry of Health to conduct the present study, enrolling 1601 women from eight facilities (one peri-urban and three urban hospitals and four maternal–child health family planning clinics) located in Northern, Central and Southern Vietnam. The study sought to provide answers to critical questions about the feasibility of introducing medical abortion at different types of public health facilities within the healthcare system and to test innovations to the regimen (such as a reduced mifepristone dose and home use of misoprostol) more widely to gauge their appropriateness for national adaptation.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

This study took place in eight facilities across Vietnam from January to December 2001. Women who met the study's inclusion criteria, selected medical abortion and consented to participate were recruited at three urban tertiary hospitals, one peri-urban district hospital and four urban state-run family planning clinics. Surgical abortion services were already in place in each of the study sites. Providers at three facilities, two urban hospitals and one urban family planning clinic, had previous experience with medical abortion in clinical studies and all of the sites had previously participated in clinical research.

All participants had intrauterine pregnancy less than 56 days LMP, and had no known allergies to mifepristone or misoprostol. Women were expected to live or work within an hour of the study clinic and be willing to return for at least one follow up visit. Gestational age was assessed using one or more standard methods, including physical examination, menstrual history, ultrasound and β-hCG. Use of ultrasound was not obligatory in the study protocol, but most providers choose to use it whenever possible.

Women who met the inclusion criteria and chose to participate signed a written informed consent form and were given 200 mg mifepristone orally in the clinic. During this initial visit, all women were given the choice either to return to the clinic in two days to take their misoprostol or, if they preferred, to take their misoprostol at home. According to the study protocol, the first 20 women at each site, with the exception of three sites having previous experience with medical abortion, administered their misoprostol at the clinic. This was required as a means to allow new providers greater familiarity with the experience of medical abortion to better understand, and therefore, better respond to, any questions or side effects following misoprostol administration. Only one of the five novice sites, the peri-urban district hospital, strictly followed this guideline. Women choosing home administration of misoprostol were given two tablets of 200 μg misoprostol as well as eight 500 mg tablets of paracetamol to manage their pain at home. They were instructed to take the misoprostol in two days and to take the pain medication as needed. Given misoprostol's unique hexagonal shape and blister packaging, and most women's familiarity with paracetamol, it was easy for women to distinguish between the two types of tablets. Women choosing to return to the clinic for their misoprostol were given an appointment two days later to take their pills in the presence of the study clinician. Women who chose home administration of misoprostol were told that they could return to the clinic to take the medication if they changed their minds.

All women were given a diary to record the number of days and intensity of bleeding and side effects. They were also given detailed instructions about what to do in the event of an emergency and the number of a clinic hotline. Each study site set up a hotline to maintain contact with their patients. Regardless of where they chose to administer the misoprostol, all women were asked to return to the clinic in two weeks to confirm the status of their pregnancies. Abortion status was determined using clinical exam, which sometimes included ultrasound. Use of ultrasound was not required by the protocol, but instead was to be used on an ‘as needed’ basis by study providers. Women who administered misoprostol at home were asked to confirm that they swallowed the tablets given to them. In addition, all women were asked to record the date and time that they administered misoprostol on their diary cards. Women with complete abortions were discharged from the study at this time. Women presenting with incomplete abortions were offered the choice of waiting an additional week to check the status of their abortions or, if they preferred, to undergo a surgical termination. Surgical interventions were offered to all women presenting with ongoing pregnancies. Medically indicated surgical terminations were also provided if women needed haemostatic control or presented with an infection during the study period. Standard terminology as outlined in the literature was used to classify abortion status.9 Data collected from the 37 women who did not complete the protocol and were lost at follow up at any time during the study were excluded from the analysis. Strenuous attempts were made to contact women who were lost at follow up, including contacting women at home, if phone access was possible, and sending study personnel to homes, if addresses were available.

The study was designed to gather data about women's experiences with this simplified medical abortion regimen. Research tools recorded clinical outcome as well as women's reasons for selecting medical abortion, side effects experienced and overall acceptability of the method. Acceptability data were collected during recruitment and later at an exit interview via semistructured questions. Special attention was paid to the management of side effects and women's experiences outside of the clinic, such as phone calls to the study hotline, additional clinic visits and whether the woman had companionship (such as a family member or friend) during the abortion process. Data entry and analysis were conducted using the Standard Program for Social Scientists (SPSS), Version 11. χ2, t test and regression analyses were used as appropriate and statistical significance was defined as P < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Given the interest in home use medical abortion regimens, data are presented by site of misoprostol administration where experiential differences occurred between the two user groups. A significantly larger majority of women selected home (88.9%, n= 1380) as opposed to clinic (11.1%, n= 174, P < 0.001) use of misoprostol; 71.3% of all clinic users (n= 121) were recruited at the peri-urban centre participating in this study. The background characteristics of women participating in the study are shown in Table 1.

Table 1.  Participant characteristics.^
 All users (N= 1564)Home users (n= 1390)Clinic users (n= 174)P
  • ^

    Does not include cases that did not complete the protocol: (a) lost to follow up (n= 24): (b) did not take misoprostol (n= 13).

Age (mean years)29.729.828.3 
Age (range years)18–4818–4819–47 
Years of education (mean)10.911.18.7<0.001
Married (%)89.6 (1402)89.5 (1244)90.8 (158) 
Gestational age in days (mean)42.442.243.70.001
Gravidity (mean)2.82.82.2<0.001
Primigravida (%)9.8 (154)9.0 (125)16.7 (29)0.001
First abortion (%)48.1 (752)47.7 (663)51.1 (89) 

When asked why they opted for medical abortion, women were unanimous in declaring their desire to avoid pain and surgery. These views were consistent, with nearly half of the study population reporting that they selected medical abortion because they perceived it as a less painful (49.3%, n= 771), safer method with fewer complications (35.2%, n= 550) than surgical abortion. Women appreciated that medical abortion enabled them to avoid surgery (30.4%, n= 475). The ease and simplicity (31.5%, n= 492) of the method as well as a perception that this new (medical) method was better than the older (surgical) means of pregnancy termination (16.1%, n= 251) were also desired features of medical abortion that appealed to women in this study.

Eight-nine percent of women in this study (home users: 88.6%, n= 1231; clinic users: 94.3%, n= 164, P= .002) had successful abortions using this simplified medical abortion regimen (Table 2). Few women presented with a confirmed ongoing pregnancy (home users: 3.1%, n= 43; clinic users: 0.6%, n= 1, P= .058). Rates of incomplete abortion were higher than expected, with 5.8% (n= 81) of home users and 3.4% (n= 6) of clinic users presenting at the clinic with an incomplete abortion (P= 0.197). A minority of women terminated their abortion surgically during the study period by personal choice or provider recommendation (1.3%, n= 20) and fewer still were given a medically indicated surgical termination (1.2%, n= 18). An additional 13 women (0.08%) did not complete the study protocol and were given a surgical intervention to complete their abortions. Providers at each study site adhered to a strict protocol with regard to follow up, and all women were counselled to return to confirm the status of their pregnancy. Very few women (home = 1.5% [24]; clinic = 0.0% [0]) were lost to follow up.

Table 2.  Efficacy and adjusted odds ratio for success by study site.*P= 0.004.
Study siteEfficacy (%, n)OR95% CI
  • *

    Does not include cases that did not complete the protocl: (a) lost to follow up, (b) did not take the misoprostol.

  • ^

    Previous medical abortion experience.

Urban MCH/FP clinic^91.5 (183/200)1.0 
Urban tertiary hospital85.1 (166/195)0.90.4–1.7
Urban MCH/FP clinic83.7 (159/190)0.50.3–0.9
Urban tertiary hospital^90.8 (177/195)0.50.3–1.0
Urban MCH/FP clinic91.2 (176/193)0.40.2–0.7
Urban tertiary hospital^85.0 (170/200)0.90.4–1.8
Urban MCH/FP clinic92.3 (177/191)0.80.4–1.5
Peri-urban district hospital93.5 (187/200)1.30.6–2.7

As shown on Table 2, there was a statistically significant variation among success rates at the eight study facilities (range: 83.7% to 93.5%, P= 0.004). One facility, the peri-urban district hospital, had the highest overall success rate (93.5%), the largest proportion of clinic users (71.3% of the entire clinic cohort) and lost no women during follow up.

Regression using univariable analysis was performed to explore whether demographic factors, location of misoprostol administration or study site affected the success rate in this study. No association was found linking success to location of misoprostol administration, gestational age, schooling or marital status; however, a positive association was identified between likelihood of success and first abortion (P= 0.003) and study site (P= 0.004) (Table 2). Although not statistically significant at P= 0.05, success was also associated with younger age (P= 0.067). In contrast to earlier reports indicating decreased efficacy with greater gestational age, in this study efficacy remained consistent across gestational age group (28–35 days: 88.0%; 36–42 days: 87.2%; 43–49 days: 91.1%; 50–56 days: 88.5%). Women with higher reported gravidity (mean gravidity was 3.31 for failures and 2.69 for successes) were significantly more likely to have a failed medical abortion (P < 0.001).

With the exception of the first participants recruited at sites without previous medical abortion experience, each woman could choose to take her misoprostol at home or at the clinic. Table 3 shows tabulations of women's reasons for choosing either home or clinic misoprostol administration. Home users were also queried to learn if they were alone when they took their misoprostol. Contrary to concerns of women being alone when they swallowed the drug, nearly three-quarters (73.4%, n= 1014) reported that they were with someone when they took their misoprostol, mostly with husbands/boyfriends (74.6%, n= 756) and fewer with other family members (12.5%, n= 127), mothers (11.6%, n= 118) or friends (6.8%, n= 69).

Table 3.  Reasons for selecting site of misoprostol administration. Values are expressed as n (%).
 Home users (n= 1389)Clinic users (n= 174)
  • Women could give up to two reasons.

Easier, simpler, faster800 (57.6)5 (2.9)
More compatible with household/professional duties449 (32.2)4 (2.3)
More autonomy (‘self-controlled’)293 (21.1)0 (0.0)
Less travel, no time or money for additional clinic visits211 (15.2)2 (1.1)
More secret, confidential205 (14.8)12 (6.9)
Prefer to be at home/avoid clinic199 (14.3)2 (1.1)
Perceived as safer160 (11.5)19 (10.9)
No worries87 (6.3)132 (75.9)
Concern about correctly following regimen11 (1.0)18 (10.3)
Wants to be near healthcare staff3 (0.2)126 (72.4)

Study participants did not experience any serious complications at a result of their medical abortions. Two women experienced allergic reactions, one following administration of mifepristone and the other following administration of misoprostol. Each woman had a temporary skin rash that was easily treated with chlorpheniramine per os at the study facility on an outpatient basis. No blood transfusions were given to participants, although there were three instances of heavy bleeding requiring surgical intervention.

All women were asked to keep a diary to record the pain and side effects that they experienced during the two-week period following the initial clinic visit (Table 4). On average, women reported that they bled for approximately 10 days. Bleeding patterns were similar in the two groups, with home users reporting a slightly greater number of days of spotting than clinic users (home: 4.9; clinic: 4.4, P= 0.048). Women reported few side effects, such as pain, nausea and cramping, and indicated that these effects rarely lasted longer than two days. Nearly all of the women (99.7%, n= 1562) reported that the pain medication (paracetamol) provided by the study team enabled them to manage their pain successfully.

Table 4.  Women's reports of bleeding and side effects. Values are expressed as mean.
 Home users (n= 1381)Clinic users (n= 174)P
Bleeding (mean days)
All bleeding9.99.9 
Heavy bleeding (>period)2.52.4 
Normal bleeding (like period)3.33.3 
Light bleeding (<period)4.94.40.048
 
Other side effects (mean days)
Nausea1.50.8<0.001
Vomiting0.60.2<0.001
Pain/cramps1.71.40.013
Fever/chills0.40.0<0.001

Additional follow up care requested by each group of women was examined as an indication of how they managed any abortion-related side effects. In this respect, home users were more likely to call the study hotline (15.5%, n= 216 vs 6.9%, n= 12, P= 0.002) and make unscheduled clinic visits (9.0%, n= 126 vs 4.6%, n= 8, P= 0.047).

At the follow up visit, women were asked several acceptability questions relating to their use of the method. Women's reports of the method's best and worst features are shown in Table 5. To gauge their comfort with home use medical abortion, each woman was also asked where she would choose to take the misoprostol in the event that she ever needed another medical abortion. Nearly all of the home users (96.1%, n= 1328) indicated that they would again select home administration of misoprostol, while a small percentage (2.0%, n= 27) stated that they would switch to clinic administration for a future medical abortion. Clinic users were more likely to change the place of misoprostol administration for a future medical abortion: 38.5% (n= 67) of clinic users indicated that they would swallow the drug at home in the future. The remaining 61.5% (n= 107) of clinic users said that they would repeat the same protocol, taking their misoprostol at the clinic again for future medical abortions.

Table 5.  Best and worst features of medical abortion. Values are expressed as n (%).
 All users
Best features (n= 1545)
Easier, simpler, more convenient811 (52.5)
Perceived less pain518 (33.5)
No surgery, fear surgery255 (16.6)
Successful in completing abortion223 (14.4)
Perceived as safer, healthier220 (14.2)
Secret, more confidential203 (13.1)
No complications, negative health risks1919 (12.4)
No best feature144 (9.3)
Less anxiety, fewer worries81 (5.2)
 
Worst features (n= 1554)
Bleeding786 (50.6)
None, no reason given419 (27.0)
Pain and cramps300 (19.3)
Fatigue207 (13.3)
Nausea/vomiting187 (12.0)
Fear/anxiety98 (6.3)
Procedure takes too long/too many visits112 (7.2)
Failed abortion78 (5.0)
Other reason34 (2.2)

When asked to rate their overall satisfaction with medical abortion, most women reported that they were either ‘very satisfied’ (home: 35.2%, n= 484; clinic: 24.7%, n= 43) or ‘satisfied’ (home: 48.4%, n= 666; clinic: 66.7%, n= 116) with the method. A relatively smaller percentage of women reported that they were neutral towards the method (home: 9.4%, n= 129; clinic: 5.2%, n= 9), unsatisfied (home: 6.7%, n= 92; clinic: 3.4%, n= 6) or very unsatisfied (home: 0.3%, n= 4; clinic: 0.0%, n= 0). There were no statistically significant differences in satisfaction ratings between women in the two user groups.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

The appeal of medical abortion in Vietnam is apparent from the results of this study: nearly 90% of women successfully aborted and satisfaction levels were high with the method. Study results were presented to the Ministry of Health's Scientific Committee in March 2001 and provided the scientific basis from which the method was approved for use in Vietnam. Newly updated national reproductive health guidelines include instructions on the provision of medical abortion within the country's healthcare system. In an effort to guide the introduction of the method both in Vietnam and elsewhere, it is useful to apply lessons learned from this study to steer towards appropriate medical abortion service delivery, including attention to the appropriateness of the level of healthcare facility, home use regimens, training and supervision.

In this study, women were recruited at secondary and tertiary healthcare facilities, and no difficulties were linked to the level of the healthcare facility. The experience of the one peri-urban district level facility in this study demonstrates quite clearly that district level facilities, when given the proper training, are equipped to offer safe medical abortion services. Indeed, the success rate at this facility was higher than that of any facility in which new providers were using the method. Providers in this setting were most likely to achieve full protocol compliance, which is evidenced by the fact that no women were lost to follow up at this facility.

The home use regimen was very popular among women in this study. Overall, home users tended to be pleased with their choice of regimen and the majority reported that if they needed future medical abortions, they would select home administration again. Given that no serious complications were experienced by the nearly 1400 women who selected the home use regimen and that most home users were accompanied by a close family member who could presumably help them to arrange back up care (if needed), it seems reasonable that this regimen option be offered to women.

The overall success rate in this study is slightly lower than that of previously reported medical abortion studies in Vietnam.3,5 The data show positive associations between two characteristics of the study population: first abortion and study site. Data from a recently published meta-analysis of medical abortion efficacy illustrate the association between first abortion and medical abortion success, showing that the odds of having a successful medical abortion are 15% higher among women having their first abortion.10 While there was no association between successful abortion and level of healthcare facility in this study, that likelihood of success was strongly linked to specific study site. The apparent association between study site and successful medical abortion was also identified by Hedley et al.,10 leading them to emphasise the importance of individual providers and study sites for success. In this study, an association between success and woman's age (P= 0.067) was identified, showing a tendency towards higher likelihood of success among younger women.

Discussions among the study team and with other providers in Vietnam seem to indicate that the success rate found in this study is likely a better picture of what may happen when medical abortion is introduced on a larger scale in new settings globally. For instance, in this study, new medical abortion providers, regardless of level of facility, tended to report a greater number of incomplete abortions requiring surgical intervention in the early phases of recruitment. This effect may be partly attributable to the fact that study sites without previous medical abortion experience did not strictly comply with the protocol guideline specifying that the first 20 women at a new site should be given misoprostol at the clinic. Instead, they let women administer misoprostol at home right away but then often relied on ultrasound readings, rather than clinical assessment, to determine success. These protocol guidelines had been set forth to enable new providers to learn about the medical abortion process and to gain perspective on the normal process of medical abortion. Later, with greater experience, and in some instances, additional training, providers were increasingly confident in the method, which led to fewer unnecessary surgical interventions in some of the study sites. As the study neared completion, providers at several study sites re-evaluated their previous cases and identified instances in which they may have intervened unnecessarily and given women surgical treatment that was not needed.

Providers felt that training, oversight during recruitment and previous experience with medical abortion technology all factored in to comfort with the method and, likely, successful outcomes at their particular locations. Provider training is a critical element for successful introduction of medical abortion in new settings. As the method becomes used widely, well-defined training modules will be needed for local use, and centres with previous medical abortion experience should be made key reference points for training new providers throughout the country. During training, particular attention should be given to the medical abortion protocol and appropriate use of ultrasonagraphy in determining pregnancy status. Given that both sonographers and clinicians are responsible for providing ultrasonographic exams in many parts of the world, it is critical that each group of providers is instructed in proper use of ultrasound in medical abortion. Incorrect or overuse of ultrasound should be addressed in detail during these trainings. As seen in this study, providers who rely too heavily on ultrasound images to determine complete abortion run the risk of intervening surgically more often than is necessary. Training modules should include case studies of uteri with debris that will evacuate naturally, and do not require surgical completion. Diagnosis of true ongoing pregnancy via ultrasound should also be closely reviewed, as providers in this study also may have misdiagnosed cases of ongoing pregnancy. Additionally, training courses must move beyond simply providing a theoretical overview of medical abortion to include observation of actual medical abortion users and mentorship with experienced providers.

Overall, the findings from this study strongly support the introduction of medical abortion to facilities at a range of levels of the healthcare system. While there are several service delivery implications that must be adequately addressed via training and supervision, research has demonstrated safety, efficacy and popularity of the method among women and providers. In Vietnam, the method has been approved and is featured in the country's National Technical Guidelines in Reproductive Health. The stage is now set to take the lessons learned from this study and apply them in new settings as part of a larger effort to make medical abortion widely available to women worldwide.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

The authors would like to thank all the women who participated in this study and each of the local investigators who provided their care, including Dr Nguyen Duc Vy, Dr Nguyen Thi Hue and Dr Nguyen Thi Hong Minh at the Institute for the Protection of Mother and Newborn (IPMN) in Hanoi; Dr Pham Minh Tam, Dr Nguyen Thi Nghiem and Dr Pham Hong Hanh at the MCH/FP Hanoi; Dr Dao Thi Chut and Dr Pham Thi Thu Hanh at the MCH/FP Haiphong; Dr Nguyen Thi Loi, Dr Bui Thi Chi and Dr Nguyen Khoa Nguyen at the MCH/FP Thua Thien in Hue; Dr Chu Hoang Khanh Huong, Dr Le Thi Sau and Dr Hoang Dieu Hien at Danang General Hospital; Dr Au Nhut Luan and Dr Nguyen Thi Bach Nga at Hung Vuong Hospital in Ho Chi Minh City; Dr Huynh Thi Trong, Dr Tran Kim Nguyet and Dr Pham Minh Tam at the MCH/FP in Ho Chi Minh City; Dr Le Thi Hanh, Dr Phan Thi My Duyen and Dr Do Kim Hoang at Hocmon District Hospital in Ho Chi Minh City. In addition, we are extremely indebted to Dr Le Kim Ba and Ms Samantha Lobis for their efforts to carefully enter and clean the data set, Dr. Nguyen Thi Thom, Center for Population Studies and Information of the National Committee for Population and Family Planning (NCPFP) for translating selected questions from interview forms from Vietnamese into English, Dr Shelley Clark for her work during the initial phases of this study and Ms Batya Elul for her helpful comments on this manuscript.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Accepted 26 March 2004