WHO guide to good prescribing is 25 years old: quo vadis?

INTRODUCTION: Twenty-five years ago, the World Health Organization (WHO) published the Guide to Good Prescribing (GGP), followed by the accompanying Teacher's Guide to Good Prescribing (TGGP). The GGP is based on a normative 6-step model for therapeutic reasoning and prescribing, and provides a six-step guide for students to the process of rational prescribing. METHOD: We reviewed the need to update both WHO publications by evaluating their use and impact, including new (theoretical) insights and demands. Based on information from literature, Internet, and other (personal) sources, we draw the following conclusions. RESULTS: 1. An update of the GGP and TGGP, both in terms of content and form, is necessary because of the current need for these tools (irrational medicine use and unavailability of medicines), the lack of similar documents, and the lack of connection with recent developments, such as Internet and modern education; 2. The basic (6-step) model of the GGP is effective in terms of rational prescribing in the undergraduate situation and is still consistent with current theories about (context) learning, clinical decision-making, and clinical practice; 3. The dissemination and introduction of the GGP and TGGP in education has been successful so far, but is still not optimal because of lack of support and cooperation. CONCLUSIONS: On the basis of the evaluation results, a plan for the revision of the GGP and TGGP is presented.

Should medical students learn to develop a personal formulary? An international, multicentre, randomised controlled study.

OBJECTIVE: This study was performed to determine whether students who are trained in developing a personal formulary become more competent in rational prescribing than students who have only learned to use existing formularies. METHODS: This was a multicentre, randomised, controlled study conducted in eight universities in India, Indonesia, the Netherlands, the Russian Federation, Slovakia, South Africa, Spain and Yemen. Five hundred and eighty-three medical students were randomised into three groups: the personal formulary group (PF; 94), the existing formulary group (EF; 98) and the control group (C; 191). The PF group was taught how to develop and use a personal formulary, whereas e the EF group was taught how to review and use an existing formulary. The C group received no additional training and participated only in the tests. Student's prescribing skills were measured by scoring their treatment plans for written patient cases. RESULTS: The mean PF group score increased by 23% compared with 19% for the EF group (p < 0.05) and 6% for controls (p < 0.05). The positive effect of PF training was only significant in universities that had a mainly classic curriculum. CONCLUSION: Training in development and use of a personal formulary was particularly effective in universities with a classic curriculum and with traditional pharmacology teaching. In universities with a general problem-based curriculum, pharmacotherapy teaching can be based on either existing or personal formularies.

Ten recommendations to improve use of medicines in developing countries.

Inappropriate prescribing reduces the quality of medical care and leads to a waste of resources. To address these problems, a variety of educational and administrative approaches to improve prescribing have been tried. This article reviews the experiences of the last decade in order to identify which interventions have proven effective in developing countries, and suggests a range of policy options for health planners and managers. Considering the magnitude of resources that are wasted on inappropriately used drugs, many promising interventions are relatively inexpensive. Simple methods are available to monitor drug use in a standardized way and to identify inefficiencies. Intervention approaches that have proved effective in some settings are: standard treatment guidelines; essential drugs lists; pharmacy and therapeutics committees; problem-based basic professional training; and targeted in-service training of health workers. Some other interventions, such as training of drug sellers, education based on group processes and public education, need further testing, but should be supported. Several simplistic approaches have proven ineffective, such as disseminating prescribing information or clinical guidelines in written form only. Two issues that will require a long-term strategic approach are improving prescribing in the private sector and monitoring the impacts of health sector reform. Sufficient evidence is now available to persuade policy-makers that it is possible to promote rational drug use. If such effective strategies are followed, the quality of health care can be improved and drug expenditures reduced.

Can hysterosalpingocontrast-sonography replace hysterosalpingography in the assessment of tubal subfertility?

INTRODUCTION: Hysterosalpingo-contrastsonography (HyCoSy) is a new method for assessing tubal patency using transvaginal ultrasound. It is thought to have several advantages over conventional hysterosalpingography (HSG). We prospectively evaluated the performance of HyCoSy and HSG in the diagnosis of tubal pathology. METHODS AND PATIENTS: One-hundred consecutive subfertile women underwent both HyCoSy and HSG in randomised order. Results of both tests were related to findings at laparoscopy with dye, which was used as the reference test. Each woman was asked to score the pain exsperienced at both procedures on a visual analogue scale. RESULTS: When laparoscopy with dye was used as reference test, the likelihood ratios of HyCoSy were slightly inferior to those obtained for HSG. Since the performance of HyCoSy was dependent on experience, the results were recalculated omitting the 50 initial procedures from the analysis. In that calculation, results of HyCoSy and HSG were comparable. There were no differences in pain experienced during the procedure, as there appeared also to be no differences in patient preferences. CONCLUSION: There appear to be no strong arguments either to replace HSG by HyCoSy, or to reject the use of HyCoSy. Both procedures can be used in the evaluation of tubal pathology.

[Pregnancy course and outcome in 2956 pregnancies after in-vitro fertilization in Netherlands]. / Beloop en uitkomst van 2956 zwangerschappen na in-vitrofertilisatie in Nederland.

OBJECTIVE: Description of the outcome of pregnancies after in vitro fertilisation (IVF) in Dutch IVF centers. DESIGN: Descriptive, retrospective. METHOD: Data were collected on IVF pregnancies in the period 1984-1992 from seven Dutch IVF centers. RESULTS: The study comprised 2956 pregnancies. Five centres provided data on 2133 ongoing and non-ongoing pregnancies. More than 25% ended in a spontaneous abortion (22.3%) or ectopic pregnancy (3.6%). From the seven centres there were data available on 2311 ongoing pregnancies. Of these, 30.8% were multiple; preterm delivery occurred in 29.2%. The birth weight of 40.6% of 3173 neonates was lower than 2500 g and that of 10.1% lower than 1500 g. A birth weight under the 10th percentile of the national reference curve was found in 16.7% and under the 2.3rd percentile in 4.3% of cases. Perinatal mortality was 31.3 pro mille. In 1588 singleton pregnancies preterm birth occurred in 15.6%; 41.3% of the singletons weighed less than 2500 g, of which 3.6% less than 1500 g while 12.3% had a birth weight below the 10th percentile. The results of our study are similar to those of other major studies in the literature and are unfavourable compared with to Dutch reference values. This is mainly due to the high proportion of multiple pregnancies. However, we found indications of a slight disturbance of pregnancy in IVF singleton and twin pregnancies.

Intervention research in rational use of drugs: a review.

Many studies have been done to document drug use patterns, and indicate that overprescribing, multi-drug prescribing, misuse of drugs, use of unnecessary expensive drugs and overuse of antibiotics and injections are the most common problems of irrational drug use by prescribers as well as consumers. Improving drug use would have important financial and public health benefits. Many efforts have been undertaken to improve drug use, but few evaluations have been done in this field. This article provides an overview of 50 intervention studies to improve drug use in developing countries. It highlights what type of interventions exist and what is known about their impact. It reveals that commonly used interventions, such as an essential drug list and standard treatment guidelines, have rarely been systematically evaluated so far. The majority of intervention studies are focused on prescribers in a public health setting, while irrational use of drugs is also widespread in the private sector. Furthermore, the magnitude of inappropriate drug use at community level is often overlooked and few interventions address drug use from a consumer's perspective. More research on different types of intervention strategies in various health care settings is needed to draw conclusions on the effectiveness of a specific intervention strategy. Also more research is needed on socio-cultural factors influencing the impact of drug use interventions, particularly from a user perspective. To enhance evaluative research, more technical support will be needed for researchers in developing countries. The design of available studies from developing countries is generally weak, only six of the 50 studies included in this overview were randomized controlled studies. In order to provide technical support and coordination of future intervention research the establishment of an international resource centre for drug use intervention research is recommended.

A prospective, randomized, cross-over comparison of two methods of artificial insemination by donor on the incidence of conception: intracervical insemination by straw versus cervical cap.

In a prospective, randomized study of insemination with donor semen, intracervical insemination by straw was compared with insemination using a cervical cap with an intracervical reservoir. A total of 91 patients completed 486 treatment cycles. There were no significant differences in age, parity, indication for insemination by donor, or method of cycle monitoring between women who became pregnant and those who did not conceive with either insemination method. In 236 standard intracervical insemination cycles, 14 patients became pregnant (5.9% per cycle), whereas 38 patients conceived in 250 cervical cap cycles (15.2% per cycle). Both the crude pregnancy rates and the cumulative pregnancy rates calculated by the Kaplan-Meier life-table method were significantly different (chi(2)-test, P < 0.001, and log-rank test, P < 0.005 respectively). Pregnancy rates in artificial insemination with cryopreserved donor semen may be improved by the use of a cervical cap when compared to cervical insemination by straw. The use of the cervical cap may prolong the exposure of the spermatozoa to the cervical mucus and prevent the backflow of semen into the vagina.

Guidelines for drug donations.

Drug donations are usually given in response to acute emergencies, but they can also be part of development aid. Donations may be given directly by governments, by non-governmental organisations, as corporate donations (direct or through private voluntary organisations), or as private donations to single health facilities. Although there are legitimate differences between these donations, basic rules should apply to them all. This common core of "good donation practice" is the basis for new guidelines which have recently been issued by the World Health Organisation after consultation with all relevant United Nations agencies, the Red Cross, and other major international agencies active in humanitarian emergency relief. This article summarises the need for such guidelines, the development process, the core principles, and the guidelines themselves and gives practical advice to recipients and donor agencies.

Diagnosis of ectopic pregnancy after in vitro fertilization and embryo transfer.

OBJECTIVE: The combination of transvaginal sonography and serum hCG measurement is reliable in the diagnosis of ectopic pregnancy (EP) in spontaneous pregnancies. In patients who became pregnant through IVF-ET, transfer of multiple embryos after IVF could be responsible for the different performance of these tests. We evaluated the discriminative capacity of transvaginal sonography in combination with hCG measurement in the diagnosis of EP after IVF-ET. DESIGN: Prospective cohort study. SETTING AND PATIENT(S): Consecutive patients, pregnant through IVF-ET, who presented with clinically suspected EP. INTERVENTION(S): Transvaginal sonography, serum hCG measurement at 6, 9, and 15 days after ET and after a negative transvaginal sonography. MAIN OUTCOME MEASURE(S): Ectopic pregnancy confirmed at laparoscopy. RESULT(S): Between September 1993 and May 1996, 86 women were included in the study, of whom 24 had an EP. Transvaginal sonography identified 46 intrauterine pregnancies and 5 EPs, but serum hCG could not diagnose EPs in patients in whom transvaginal sonography did not show a gestational sac. Serum hCG measurement 9 days after ET could identify pregnancy failure with 100% specificity at a cut-off value of 18 IU/L, but it could not identify patients with EP with enough certainty to justify immediate treatment. CONCLUSION(S): We recommend single serum hCG measurement 9 days after ET to discriminate between viable and nonviable pregnancies. Transvaginal sonography can be postponed until 5 weeks after ET, except for patients with abdominal pain and/or vaginal bleeding, or patients with a serum hCG level of < 18 IU/L.

Instability of (methyl)ergometrine in tropical climates: an overview.

Parenteral ergometrine is widely used for the prevention and treatment of excessive uterine bleeding following birth. Unfortunately, in tropical climates it is often found to contain very little active ingredient: only 32 of 100 field samples from Bangladesh, Gambia, Malawi, Yemen and Zimbabwe contained 90-110% of the amount of active ingredient stated on the label, and 34 contained less than 60%. In this paper the results of nine studies, of which eight were initiated and coordinated by WHO, are reviewed to formulate answers to the following questions: (1) what is the extent of the problem of low potency of ergometrine in tropical climates; (2) is the problem due to instability or low initial quality, or both; (3) which practical measures can assure the quality of injectable ergometrine; and (4) are there any alternative drugs which are more stable? Injectable ergometrine is very unstable under tropical conditions and particularly if stored unrefrigerated and exposed to light, when it may loose up to 20% of its potency per month. However, there are differences between brands. Practical measures to assure the quality of injectable ergometrine therefore include a careful supplier selection and refrigerated storage. Ergometrine injection should always be protected from light until given to the patient. Loss of active ingredient can easily be detected by regular visual checks of the colour of the solution. Any discoloration implies that the solution contains less than 90% of the stated amount of active ingredient, and should not be used. Methylergometrine is no more stable than ergometrine. Parenteral oxytocin is more stable than both ergometrine and methylergometrine injection. Oral and buccal dosage forms are less stable than injections. In view of the better stability in tropical climates, similar cost, fewer side effects and comparative efficacy, parenteral oxytocin, rather than parenteral ergometrine, is the drug of choice in the prevention and treatment of postpartum haemorrhage.

Progesterone alone versus progesterone combined with HCG as luteal support in GnRHa/HMG induced IVF cycles: a randomized clinical trial.

Two different regimens of luteal support in gonadotrophin hormone-releasing hormone (GnRH) analogue/human menopausal gonadotrophin (GnRHa/HMG)-induced in-vitro fertilization cycle (IVF) were compared in a randomized clinical trial. After embryo transfer, either vaginal progesterone alone was administered (n = 89, P group), or a combination of vaginal progesterone and human chorionic gonadotrophin (n = 87, P/HCG group). The primary aim of this study was to assess the effect of the different regimens of luteal support on the pregnancy rate. The secondary aim was to compare oestradiol and progesterone concentrations in the luteal phase between the two groups, and assess their effect on the pregnancy rate. A clinical pregnancy rate of 15% was found in the P/HCG group in comparison with 26% in the P group (odds ratio 0.49; 99% confidence interval: 0.18-1.3). The luteal serum oestradiol and progesterone values in the P/HCG group were significantly higher when compared with the P group on the 6th, 9th and 12th day after oocyte retrieval (Wilcoxon P < 0.001). In accordance with the high oestradiol concentrations, more cases of ovarian hyperstimulation syndrome (OHSS) were found in the P/HCG group. Oestradiol values on the 9th day after oocyte retrieval, presumably the day of implantation, appeared to be higher in women who did not become clinically pregnant. We conclude that vaginal progesterone alone provides sufficient luteal support in GnRHa/HMG induced IVF cycles. The combination of vaginal progesterone and HCG as luteal support leads to significant high luteal oestradiol and progesterone concentrations. But a high concentration of oestradiol seems to have a deleterious effect on the implantation process, resulting in a low pregnancy rate.

Socio-economic characteristics of artificial insemination donor (AID) couples compared with matched population controls.

Socio-economic characteristics like education, occupation and religion may play a role when choosing or refraining from treatment by artificial insemination by donor (AID). From a cohort of 189 AID-patients, the socio-economic characteristics were established from the notes and a questionnaire that was sent to all patients to complete the available data. The response rate to the questionnaire was 83.6% (158 women). Data were compared with population controls that were matched for age and region. AID patients in this study had significantly lower educational and/or occupational levels than matched population controls and were significantly more religious.

Impact of a short course in pharmacotherapy for undergraduate medical students: an international randomised controlled study.

Irrational prescribing is a habit which is difficult to cure. However, prevention is possible and for this reason the WHO Action Programme on Essential Drugs aims to improve the teaching of pharmacotherapy to medical students. The impact of a short problem-based training course in pharmacotherapy, using a WHO manual on the principles of rational prescribing, was measured in an international multi-centre randomised controlled study of 219 undergraduate medical students in Groningen (Netherlands), Kathmandu (Nepal), Lagos (Nigeria), Newcastle (Australia), New Delhi (India), San Francisco (USA), and Yogyakarta (Japan). The manual and the course presented the students, who were about to enter the clinical phase of their studies, with a normative model for pharmacotherapeutic reasoning in which they were taught to generate a "standard" pharmacotherapeutic approach to common disorders, resulting in a set of first-choice drugs called P(ersonal)-drugs. The students were then taught how to apply this set of P-drugs to specific patient problems on the symptomatic treatment of pain, using a six-step problem-solving routine. The impact of the course was measured by tests before training, immediately after, and six months later. After the course, students from the study group performed significantly better than controls in all patient problems presented (p < 0.05). The students not only remembered how to solve old problems, but they could also apply their skills to new problems. Both retention and transfer effect were maintained at least six months after the training session in all seven medical schools. In view of the impossibility of teaching students all basic knowledge on the thousands of drugs available, this approach seems to be an efficient way of teaching rational prescribing. However, the method should be accompanied by a change in teaching methods away from the habit of transferring knowledge about the drugs towards problem-based teaching of therapeutic reasoning.

Essential drugs for ration kits in developing countries.

Since the early 1980s drug ration kits have been used to improve the supply of essential drugs to rural health facilities in developing countries. This paper evaluates some of the experiences with kit systems in Angola, Bhutan, Democratic Yemen, Guinea-Conakry, Kenya, Mozambique, Sudan, Tanzania, Uganda and Zambia in relation to the selection of drugs for the kits and their quantities and cost. Data were collected through a review of published papers, annual reports and programme evaluations, by questionnaires among field staff and interviews with key experts. In comparing the 10 programmes, 21 drugs can be identified that are used in at least two-thirds of all kits. This list may be useful for evaluation and planning purposes. Six drugs (ORS, chloroquine and 4 antibiotics) usually account for over 60% of the cost of the kit. Careful monitoring of the price and quantities of these 6 drugs can therefore be very cost-effective. In the absence of reliable data on morbidity and drug needs in the initial phases of a kit system, the median drug quantities in kits from these 10 countries may serve as a starting point. Accumulating surpluses are sometimes perceived as a serious disadvantage of kit systems, ORS, benzylbenzoate solution and iron tablets are the three drugs that have most frequently accumulated. These drugs are relatively cheap and usually have a long shelf-life; in most programmes they have been successfully redistributed to other health facilities while the kit content was being adapted. The overall financial loss due to accumulation of surpluses is therefore limited. Most programmes have reached a stable kit content within two years.

Promoting rational prescribing: an international perspective.

Irrational prescribing is a global problem. Rational prescribing cannot be defined without a method of measurement and a reference standard. The former is now available but the latter needs further development. Proven effective interventions to promote rational prescribing in developed countries are treatment protocols based on wide consultation and consensus, properly introduced and with a possibility of feedback; face-to-face education focussed on a particular prescribing problem in selected individuals; structured order forms; and focussed educational campaigns. Essential drugs lists are probably effective when based on consensus and used within a comprehensive educational programme. Printed materials alone are not effective. In most cases the usefulness of such strategies in developing countries has not been proven and should be studied. Medical education in clinical pharmacology and pharmacotherapy should be based on the practical needs of future prescribes, should include the principles of rational therapeutics and problem solving, and should immunize the students against the influences they are likely to encounter in their professional life, such as patient pressure, drug promotion and irrational prescribing by peers. Within the scope of a national formulary, specialist departments in teaching hospitals should define prescribing policies as the basis for prescribing, teaching, examinations and medical audit.

Substance use in pregnancy: do we care?

Two cohorts of substance-using women were compared retrospectively. From 1969 to 1979 a very high perinatal mortality rate (PMR 9.8%) was found among 92 polydrug-using women (1 twin excluded). Preterm delivery occurred in 25% of all pregnancies and in 30% of the children birth weight was below the 10th percentile. Nineteen women using heroin only had a worse fetal outcome (PMR 32%, preterm delivery in 47%, birth weight < 10th percentile in 42%). These results led to a strict surveillance system. In the period 1980-1989, 240 women (4 twins excluded) delivered after 16 weeks. Total fetal loss decreased to 2.1% and PMR to 0.4%, which was similar to results in controls. However, 22% of the women still delivered before 37 weeks and 27% delivered a child < 10th percentile. Methadone-using women were able to halve their dosage during pregnancy and 16 were detoxified. Multivariate analysis within the substance users of the second cohort showed that the neonatal abstinence syndrome, but not the (registered) amount of opiates used, was related to a lower birth weight. Not coping with prenatal care was related to a shorter pregnancy length. Multivariate analysis, including the controls, showed a significant relation of birth weight (345 g lower) with substance use. Also, head circumference was 0.8 cm smaller. Length of pregnancy however was related to smoking. This study shows that it is difficult to make substance users attend prenatal care, but also that women coping with prenatal care reduce substance intake. Opiate use might be responsible for lower birth weight, although not in a clear dose-response relationship, whereas lifestyle, as represented by not coping with prenatal care and the quantity of cigarette smoking, shortens the length of pregnancy.

Thyroid function and thyroid size in normal pregnant women living in an iodine replete area.

OBJECTIVE: The interpretation of the changes in thyroid hormone concentrations during normal pregnancy is a matter of debate involving, in some geographical regions, enhanced thyroid activity in early pregnancy and a hypothyroid state in the third trimester. A clinically detectable increase in thyroid size has been found in areas of mild iodine deficiency ('goitre of pregnancy'), but not in iodine replete areas. DESIGN: A prospective study. We have studied thyroid size and function in normal pregnant women living in an iodine replete area. PATIENTS: Healthy women before and during a normal pregnancy resulting from artificial insemination (n = 10) and other women during the normal menstrual cycle (n = 11), in the iodine replete area of Amsterdam. MEASUREMENTS: Thyroid volume was measured by ultrasonography. Plasma T4, free T3, free reverse T3, TSH, thyroxine binding globulin, hCG, progesterone and thyroid autoantibodies were measured. RESULTS: Thyroid volume did not change during pregnancy (data given before pregnancy and during 1st, 2nd and 3rd trimesters, respectively: 10.3 +/- 5.1, 10.6 +/- 4.4, 9.6 +/- 3.8 and 9.4 +/- 3.0 ml, NS). Free T4 and free T3 levels declined during pregnancy (13.7 +/- 2.0, 13.5 +/- 4.1, 11.2 +/- 2.8, 10.2 +/- 1.6 pmol/l, P = 0.005; 4.55 +/- 0.63, 4.64 +/- 0.88, 3.72 +/- 0.67 and 4.01 +/- 0.75 pmol/l, P = 0.003), whereas free reverse T3 levels increased during pregnancy (0.16 +/- 0.04, 0.19 +/- 0.07, 0.14 +/- 0.03 and 0.20 +/- 0.07 pmol/l, P = 0.001). Thyroglobulin levels remained unchanged. Thyroid hormones and thyroid volume did not differ between follicular and luteal phases of the menstrual cycle. CONCLUSION: Thyroid volume does not increase during pregnancy in iodine-replete areas. The decrease in free T4 and free T3 and the increase in free reverse T3 concentrations during pregnancy resemble the changes in thyroid hormones seen in non-thyroidal illness. This could be a physiological adaptation enabling energy conservation during the high metabolic demands of pregnancy.

Treatment of interstitial pregnancy with methotrexate: report of an unsuccessful case.

Until now, the traditional management of interstitial pregnancy has been surgical. Lately, we have advocated conservative treatment with methotrexate as an option for infertility patients. This is the first publication of a rupture with abundant intra-abdominal bleeding during systemic treatment with methotrexate of a patient with an interstitial pregnancy. Signs of therapy failure are discussed.