Analysis of 1071 GIFT Procedures—The Case for a Flexible Approach to Treatment

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  Analysis of 1071 GIFT Procedures—The Case for a Flexible Approach to Treatment
  1094 respiratory disease and cancer was found in the aspirin group. About 75 % of the 20 000 doctors approached by the British investigators were judged ineligible for the trial. The remaining 5000 who were recruited were therefore another selected sample, though less so than the American group. Cardiovascular events were few in British doctors (137 deaths from heart disease and 121 non-fatal myocardial infarctions, during 6 years of follow-up) compared with American doctors. PRIMARY VERSUS SECONDARY PREVENTION When the data from the American and British trials are combined (by simple addition of data), we can see that 646 subjects out of about 27 000 had died (225 from vascular disease and 421 from non-vascular disease), in contrast to about 3000 patients of the 29 000 in the meta-analysis of the Antiplatelet Trialists Collaboration.l&deg; In this report there were 497 deaths from non-vascular disease and 2431 from vascular disease: treatment with aspirin (or other antiplatelet drugs) reduced the vascular mortality rate by 15% (a small but statistically significant difference). 10 It is therefore not surprising that because of the very low event rate in both doctors’ trials no significant effect of aspirin was seen, such as that shown by meta-analysis in patients with vascular disease. The meta-analysis of 25 randomised clinical trials has shown that aspirin (and a few other antiplatelet drugs) may significantly (although not by much) reduce the incidence of fatal and non-fatal vascular disease in patients at particular risk of a new occlusive vascular event.’&deg; For example, 1000 patients with established vascular disease would have to be treated with aspirin for two years to avert 10 of 60 fatal and 20 of 60 non-fatal vascular events and 20 of 120 fatal and 30 of 90 non-fatal events in patients discharged from hospital after myocardial infarction. On the other hand, 2 primary prevention trials of aspirin in healthy doctors did not show any modification of low vascular mortality despite an overall reduction of non-fatal myocardial infarction. Thus, if these data were applied to the general population, 1000 healthy men (aged over 40) would have to take aspirin for five years to avert 8 of the 17 myocardial infarcts expected during that time ( a reduction of about 50%). Since these 17 subjects could not be identified before treatment, 983 people would have to take aspirin, in whom myocardial infarction would not develop, even without the drug-1 death from myocardial infarction would be avoided for about 850 healthy people given aspirin for five years. At present there is no case for the generalised use of aspirin (at any dose) for the primary prevention of vascular mortality in apparently healthy people. The value and safety of aspirin has not been assessed in a representative sample of a healthy population or in subjects at increased risk for cardiovascular disease. I thank Ms Cleo Colombo for help in the preparation of the script, the Italian National Research Council ("Convenzione" Istituto Mario Negri) forfinancial support, and my coworker over the past decade Manuela Livio for his support. REFERENCES 1. Smith JB, Willis AL Aspirin selectively inhibits prostaglandin production in human platelets Nature 1971; 231: 235-37 2. Hamberg M, Svensson J, Samuelsson B Thromboxanes. a new group of biologically active compounds derived from prostaglandin endoperoxides Proc Natl Acad Sci USA 1975, 72: 2994-98. 3. Moncada S, Vane JR Arachidonic acid metabolites and interactions between platelets and blood-vessel walls. N Engl J Med 1979; 300: 1142-47 4. Weiss HJ, Aledort LM Impaired platelet connective-tissue reaction in man after aspirin ingestion Lancet 1967, ii: 495-97 5. Cerletti C, Carriero MR, de Gaetano G Platelet aggregation response to single or paired aggregating stimuli after low-dose aspirin N Engl J Med 1986; 314: 316-18. 6. Beaumont JL, Caen J, Bernard J. Action h&eacute;morragipare de l’acide ac&eacute;tylsalicylique au cours des maladies du sang Bull Soc Med Hosp Paris 1955; 71: 1087. 7 Quick AJ. Bleeding problems in clinical medicine. Philadelphia: W B. Saunders, 1970. 8. Livio M, Vigano G, Benigni A, Mecca G, Remuzzi G. Moderate doses of aspirin and risk of bleeding in renal failure. Lancet 1986; i: 414-16. 9. de Gaetano G, Bertel&eacute; V, Cerletti C Pharmacology of antiplatelet drugs. In Maclntyre DE, Gordon JL, eds. Platelets in biology and pathology III. Amsterdami; Elsevier Science Publishers, 1987: 515-73. 10. Antiplatelet Trialists’ Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988; 296: 320-31 11. Steering Committee of the Physicians’ Health Study Research Group. Preliminary report: findings from the aspirin component of the ongoing physicians’ health study. N Engl J Med 1988; 318: 262-64. 12. Peto R, Gray R, Collins R, et al Randomised trial of prophylactic daily aspirin in British male doctors Br Med J 1988; 296: 313-16. 13. Clark M, Gosnell M, Hager M, Carroll G, Gordon J What you should know about heart attacks Newsweek 1988; 6: 42-46. 14. Davies MJ, Thomas A Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death N Engl J Med 1984, 310: 1137-40 15. UK-TIA Study Group United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: interim results Br Med J 1988; 296: 316-20. Occasional Survey ANALYSIS OF 1071 GIFT PROCEDURES&mdash;THE CASE FOR A FLEXIBLE APPROACH TO TREATMENT IAN CRAFT TALHA AL-SHAWAF PAUL LEWIS PAUL SERHAL ERIC SIMONS MICHAEL AH-MOYE WILLIAM FIAMANYA DAVID ROBERTSON PANKAJ SHRIVASTAV PETER BRINSDEN Fertility and IVF Unit, Humana Hospital Wellington, London NW8 9LE Summary An analysis of the outcome of first gamete intrafallopian transfers for 1071 women indicates that for those aged 40 years or more all the oocytes had to be transferred to obtain a 19&middot;2% pregnancy rate. In this age-group pregnancy rate and multiple pregnancy rate were significantly lower than those for younger women. Success rate, but not multiple pregnancy rate, was significantly higher in the group of women from whom 11 or more oocytes were recovered and transferred after ovulation induction than when only 1-4 oocytes were recovered and transferred. The findings suggest that the number of oocytes transferred should depend on clinical circumstances. INTRODUCTION BECAUSE of concern about multiple pregnancies of high order, many fertility units adhere to a policy of transferring only three, or exceptionally four, oocytes or embryos for gamete intrafallopian transfer (GIFT) and in-vitro fertilisation (IVF).12 We have expressed reservations about such a rigid code of practice, since we think that it will limit success in some women.3 These include the older woman; those who produce excessively large numbers of oocytes, often of suboptimum quality&mdash;eg, those with the polycystic ovaries (PCO); and those in whom repeated attempts at assisted reproduction have failed.  1095 Fig 1&mdash;Relation between mean number of oocytes collected and age. Numbers at top of columns refer to number of patients in relevant age-groups. We believe that multiple pregnancies resulting from IVF are more likely to occur in patients with favourable clinical features and vice versa. We think that the risk of multiple pregnancy of high order following IVF has been overestimated. An indirect index of the contribution of IVF to multiple pregnancies indicated that only 7% of triplets or above admitted to special care baby units were babies resulting from IVF. Natural conception following use of fertility drugs alone seems to be the major cause of multiple births.4 To confirm that pregnancy rates and risks of having a multiple birth of high order vary between different groups of women, we have evaluated the results of GIFT (i) in women of different ages, and (ii) in populations of patients producing different numbers of oocytes in response to ovulation induction. We have now done more than 2000 GIFT procedures and have analysed the outcome of 1500, excluding those patients who have been treated by oocyte donation. The results of 1071 first attempts at treatment are presented. The group studied includes patients in whom infertility was due to poor sperm quality. PATIENTS AND METHODS Oocytes were generally recovered by laparoscopy, although ultrasound was used on occasions when the ovary was inaccessible. Tubal gamete transfer was done laparoscopically in all cases. Ovaries were stimulated by using a combination of clomiphene citrate (’Serophene’, Serono) and either follicle stimulating hormone (’Metrodin’, Serono) or human menopausal gonadotropin (’Pergonal’, Serono). Some patients received gonadotropins after pituitary desensitisation with a luteinising hormone releasing hormone (LH-RH) analogue. Two preparations were used: (i) buserelin nasal spray (’Suprefact’, Hoechst) or goserelin subcutaneous implant (’Zoladex’, ICI). All patients were treated as day cases and pregnancy was confirmed by ultrasonography when there was amenorrhoea for 7-14 days after the predicted menstruation date. The multiple pregnancies identified and analysed in this paper are those detected on ultrasonography in the first trimester. Data were assessed mainly with regard to the effect of (i) the age of the patient and (ii) the number of oocytes transferred on the outcome of treatment. The results for the 193 (18-0%) women aged 40 years or more were compared with those of younger women, and the results for the 32 (3%) women having a multiple ovarian follicular response with the recovery and transfer of 11 or more oocytes were compared with those of women from whom fewer oocytes were recovered and transferred. Most of the latter patients had evidence of PCO as determined by a raised luteinising hormone/follicular stimulating hormone (LH/FSH) ratio, ovarian ultrasound appearances consistent with this condition, or their response to ovulation induction. These patients received 11 or more oocytes because our IVF data indicated that they have a lower fertilisation rate than other patients, while others have reported a lower pregnancy rate.5 Also, it is difficult to select the best oocytes on purely morphological criteria, and we are unaware of any definite association between PCO and the incidence of high-order multiple births following IVF. Statistical Analysis No attempt was made to correlate the outcome of treatment with the type of infertility problem, with the ovulation-induction protocol, or with variations in sperm variables, which will be reported later. Weighted non-orthogonal analyses of variance were done on the percentages shown in the tables and also on the logistic transform of those percentages. This transformation renders percentages more amenable to the analysis of variance techniques.6 All analysis of percentages showed good consistency with the analyses on the logistic transform. For ease of presentation, therefore, the results are given as percentages. Discrepancies between the percentages for the crude totals for pregnancies and abortions and the least squares estimates reported below are due to unequal numbers of patients in subclasses. RESULTS There was a reduction in the number of oocytes retrieved with increasing age (fig 1). Pregnancy and Abortion Rates Pregnancy rate varied significantly with number of oocytes transferred (p < 0.01) and the age of the patient(p < 0-05). The least squares estimates of the pregnancy rates, averaged over the number of oocytes transferred, were 40-2% for age-group <30 years, 383% for ages 30-34, 34-5% for ages 35-39, and 23-2% for ages over 40, the TABLE I-PREGNANCY RATE BY AGE-GROUP  1096 TABLE II-ABORTION RATE BY AGE-GROUP decline in pregnancy rate being especially sharp for those aged 40 and over, even though all oocytes recovered were transferred for this age-group. The least squares estimates of the pregnancy rates according to number of oocytes transferred (table 1), averaged over age-15-8% (1-2 oocytes), 25-0% (3-4), 37-5% (5-6), 41-2% (7-8), 36-3% (9-10) and 48-5% ( > 10)--reflect the expected improvement in performance with increasing number of oocytes transferred. The number of oocytes replaced did not affect abortion rate but the age of the patient did (p < 0-05). The least squares estimates of the abortion rates for the fourage-groups, averaged over oocyte replacement-22-1 % (for <30 years), 18-8% (30-34), 23-4% (35-39), and 49-1% ( > 40)--show that patients aged > 40 had an abortion rate a good deal higher than did the other patients (fig 2). Multiple Pregnancy The least squares estimates of the proportions of triplet or higher order pregnancies for the four age-groups were 4-7% (< 30 years), 4-9% (30-34 years), 2-4% (35-39 years), and 1-4% (>40 years). The declining trend with age was not statistically significant. Of the 193 patients in this age-group 154 had 3 or more oocytes transferred and 35 became pregnant. Only 1 had a triplet pregnancy, and she miscarried, and 5 had twins. The proportion of twins (3-2%) or triplets or greater (0-6%) together with the high abortion rate indicate that few high-order multiple pregnancies occur among older patients. Fig 2-Pregnancy and abortion rates. Thick line = pregnancies; thin line = abortions. Pregnancy was more than twice as common among those patients having 11 or more oocytes transferred than among those who received only 1 oocytes. Despite the small sample size of those receiving 11 or more oocytes, the proportion of them having multiple pregnancies (18-7%) was similar to that among those receiving 1 oocytes (17-3%), even allowing for the fact that approximately three times as many oocytes were replaced.Ectopic Pregnancy There is no firm evidence that the age of the patient or the number of replacements affected the likelihood of ectopic pregnancy, which occurred in 25 of the 360 patients who became pregnant (6-9%). Delivery Of the 360 patients who became pregnant, 116 have delivered, 116 patients have either aborted or had ectopic pregnancy, and 128 are still pregnant. Triplets or higher-order multiple births were detected by ultrasound in 30 (8-3%) of the 360 pregnant women. Complete spontaneous abortion occurred in 6 of these patients. The outcome of pregnancy is unknown in 2 overseas patients. Of the remaining 22 patients, 4 had selective reduction to a twin pregnancy; 2 of these have delivered, and 2 will shortly do so. 1 patient was successfully delivered of quadruplets and 10 have delivered triplets, as will 2 others shortly. In 5 other patients spontaneousreduction occurred and twins have been born. TABLE III-DENOMINATOR OF PREGNANCY RELATED TO NUMBER OF OOCYTES TRANSFERRED AND TO AGE IN 1071 GIFT TREATMENT CYCLES Findings given as number (%) pregnancies. *Number of pregnancies.  1097 DISCUSSION We understand the concerns about the possibility of multiple pregnancy resulting from fertility treatment, but we consider this association to be complex. Multiple pregnancies occur with different types of treatment, and those of higher order may occur more frequently with medical induction of ovulation than with IVF or GIFT, especially if ovarian hyperstimulation occurs. Some patients show a high pregnancy potential with fertility treatment-eg, 4 sets of quadruplets have resulted in the UK from transfer of a maximum of 4 embryos. However, other patients have repeatedly failed to become pregnant despite replacement of more than 4 embryos. The data presented in this paper show that the greatest prospect of becoming pregnant and having a multiple pregnancy with GIFT occurs when 7-10 oocytes are collected and transferred. Patients for whom collection and transfer of 7-10 oocytes are possible would also have the best results with IVF since at least 4 embryos may be available, allowing for a 60-70% fertilisation rate. Some authorities advocate transferring the same number of oocytes and embryos with assisted reproduction treatment. We disagree with this suggestion since the potential of a human oocyte cannot be equated with that of an embryo in biological terms. In addition, we think that a firm recommendation that a fixed number of oocytes or embryos be used for all patients does not take sufficient account of different clinical situations or fertility problems. Oocytes recovered for IVF have varying potentials for fertilisation and pregnancy, which depend on their maturational state.7 Those having chromosomes at the metaphase 2 stage of development give the highest fertilisation and pregnancy rates. A pregnancy may result from the use of less mature oocytes, although their capacity to be fertilised is reduced. Some abnormal oocytes, once fertilised, may produce regularly cleaving embryos, which look normal but have a lesser ability to implant.8 Regular cleaving is not a direct index of an ability to implant, nor can one accurately predict which oocytes have pregnancy potential. Research in animals has shown that although the maturation and fertilisation of oocytes is maintained with advancing age, there is a considerable increase in fetal aneuploidy because of a rising likelihood of chromosomal non-disjunction.9 The same may apply to women in late reproductive life, since they are prone to trisomic pregnancies. The reduction in fecundity rate in older women may be due in part to a relative decrease in the number of oocytes having the potential for normal fertilisation and development. The results of our clinical study confirm that fewer oocytes are produced in response to ovulation induction with increasing age. Some fertility units will not treat women over 37 years of age. However, 19 2% of our patients aged 40 or more became pregnant, provided all the oocytes were transferred. Although this pregnancy rate is significantly lower than that in younger women, we think that patients aged over 40 years should be treated provided that they are made aware of their chances of success. Restriction of the number of oocytes transferred will further reduce their chances of success and should not be necessary since their multiple pregnancy rate is lower than that in younger women. Their high abortion rate with GIFT confirms that previously reported with IVF." A flexible policy on how many oocytes or embryos should be transferred may also be required for certain specific gynaecological disorders associated with subfertility. Fertilisation rates have been reported to be reduced in patients with endometriosis." A significant reduction in pregnancy rates following IVF has been described in patients with severe endometriosis.12.13 It is possible that abnormalities of oocyte maturation may result in the formation of abnormal embryos with a defective capacity to implant. We have yet to confirm whether pregnancies can best be achieved in patients with severe endometriosis by increasing the number of oocytes or embryos transferred. Patients having a multiple follicular response often produce large numbers of oocytes of variable quality, which have been associated with a low fertilisation rate and low success with IVF. 13 However, when 11 or more oocytes were transferred with GIFT, the success rate was good despite their refractoriness to previous treatment. If women producing different numbers of oocytes had the same fertility potential, then multiple pregnancy would be expected to be much commoner in those receiving 11 or more oocytes than in those receiving fewer oocytes. However, multiple pregnancy was lower than that for most other groups. GIFT may have advantages over IVF for patients with open fallopian tubes who do not become pregnant by natural means or with conventional fertility treatment. In those in whom 7-10 oocytes were transferred there was a high success rate, and 12-4% of those becoming pregnant had three or more gestation sacs detected by ultrasound in the first trimester. However, spontaneous abortion occurred in 20% and others spontaneously reduced to lower-order pregnancy. We are unable to report the incidence of triplet or greater births until all patients are delivered. However, it is apparent that the two groups analysed have a relatively low incidence. We reiterate our previous recommendation that the number of oocytes or embryos transferred should vary with the patients’ circumstances. 14 We accept that 3 or 4 embryos may be adequate to produce a pregnancy with IVF in those with the most favourable features. If GIFT were applicable, more oocytes may need to be transferred to obtain a similar success rate since not all oocytes will be fertilised. However, not all women fall into this category. Some in whom assisted reproduction has repeatedly failed or who have certain defined clinical problems require the transfer of more oocytes or embryos to become pregnant. Future research may enable the identification of those oocytes and embryos with the best fertility potential which will allow for a more rational decision on which to transfer and which to cryopreserve. Our clinical data reported here confirm that there are advantages to using a flexible policy on the number of oocytes for transfer with GIFT, and, by inference, of embryos with IVF, to suit the individual circumstances of patients with different clinical problems. A more restrictive policy applied to all infertile patients will limit the chance of some couples ever having a child. We thank Dr D. E. Walters, Institute of Animal Physiology and Genetic Research, Babraham Hall, Cambridge, for statistical assistance; Miss E. Fincham and Miss J. Graham for help with preparation of this manuscript, and Serono Laboratories (UK) Ltd for research assistance. Correspondence should be addressed to 1. C. REFERENCES 1. Voluntary Licensing Authority Report. London. Medical Research Council, 1987. 2 Asch RH, Balmaceda JP, Ellsworth LR, Wong PC. Gamete intrafallopian transfer (GIFT) A new treatment for infertility. Int J Fertil 1985; 30: 41-45.  1098 3. Craft I, Brinsden P, Simons E. Voluntary licensing and IVF/ET. Lancet 1987; i 1148. 1148. 4 Craft I, Brinsden P, Simons E. Multiple pregnancy and assisted reproduction. Lancet 1987; ii: 692-93. 5. Romeu A, Muashar SJ, Acosta AA, Liu H, Rosenwaks Z. Hormonal and follicular behaviour of patients displaying multifollicular ovation response when undergoing IVF with different stimulation protocols. Vth World Congress of IVF and Embryo Transfer, held in Norfolk, Virginia. 1987, abstract no PP5. 6. Cox DR The analysis of binary data. London. Methuen, 1970. 7. Veeck LL. Oocyte assessment and biological performance. Vth World Congress on IVF and Embryo Transfer. Norfolk, Virginia. 1987 Abstract no PS-026. 8. Plachot M, Mandelbaum J, Junka A-M, Salat-Baroux J, Cohen J. Impairment of human embryo development after normal in vitro fertilisation. Ann NY Acad Sci 1985; 442: 336-41 9. Gosden RG Maternal age. a major factor affecting the prospects and outcome of pregnancy in in vitro fertilisation and embryo transfer. Ann NY Acad Sci 1985; 442: 45-57. 10. Romeu A, Muashar SJ, Acosta AA, et al. Results of m vitro fertilisation attempts in women 40 years of age and older: the Norfolk experience. Fertil Steril 1987; 47: 130-36. 11. Wardle PG, McLaughlin EA, McDermott A, Mitchell JD, Ray BD, Hull MGR Endometriosis and ovulatory disorder: reduced fertilisation in in vitro compared with tubal and unexplained infertility. Lancet 1985; ii. 236 12. Matson PL, Yovich JL. The treatment of infertility associated with endometriosis by in vitro fertilisation Fertil Stenl 1986, 46: 432-34. 13. Chillik CF, Acosta AA, Garcia JE, et al. The role of in vitro fertilisation in infertile patients with endometriosis. Fertil Steril 1985; 44: 56-61. 14. Craft I, Brinsden P, Simons E. How many oocytes/embryos should be transferred Lancet 1987; ii: 109-10. Round the World From our Correspondents Portugal PSYCHIATRIC TROUBLES WHEN the Portuguese Ministry of Health abruptly announced in the Press that the leading psychiatric hospital in Portugal was to close, there was much consternation. The hospital, Julio de Matos, consists of a complex of modem buildings and occupies a valuable, extensive site near the centre of Lisbon. Its existing capacity is 750 patients (500 long-stay) and it provides an acute service for Lisbon and a back-up service for patients outside the city. The behavioural therapy unit has won special renown, and the campus-style site offers various occupational and industrial therapeutic activities. No firm alternative arrangements have been proposed for the patients, other than a declared intention to move them to farms in the countryside. After the public announcement a representative from the Ministry held talks with the consultants at the hospital, and announced that Portugal either had to be in the forefront of psychiatric care or face a catastrophe. The effects of repeated budget cuts have already been felt by university departments, which are beginning to see chronic patients who had previously been treated in the hospital. In other facilities the increased pressure on beds has resulted in rapid discharge of patients in precarious social circumstances. On April 29 and 30 psychiatrists from Portugal met to discuss the issues. Prof Jean Ayme from Sainte-Anne Hospital in Paris and Dr Malcolm Weller from Friern Hospital in London were invited to provide an international perspective. A conference resolution unanimously condemned the policy as high-handed and ill-considered. A committee was convened under the chairmanship of Prof Barahona Fernandez, a disciple of Bumke, Schneider, and Kleist and the most respected figure in Portuguese psychiatry. His defence of the hospital was supported by all five professors of psychiatry in Portugal, and one enterprising patient collected 1000 signatures from members of the public objecting to the closure. A spirit of common purpose is evident throughout the medical disciplines and the Portuguese Press were at one in denouncing the proposals. Faced with this outcry, the Minister of Health, Senora Beleza, had to soften her stance, but no concrete proposals for alternative care have yet been suggested and the closure threat persists. An admiration for the policies of the British Government has been a factor in the current Portuguese strategy. In Britain, however, the all-party Parliamentary Select Committee on Social Services has expressed disquiet about hospital closures and its report is being translated for perusal by the Portuguese Government. The closure proposal was made against a background of inadequate public health facilities and a concerted attack on doctors. Over the past 18 months a barrage of abuse has driven the beleaguered doctors to an unprecedented strike action in all but emergency services. This story has its counterparts in other nations and there is a plan to hold an International Conference whereAmerican and Italian psychiatrists can join the debate and compare experience. Jamaica AN UNSCRUPULOUS ADVERTISEMENT AT the exit from Kingston, Jamaica’s international airport, is a large billboard advertising a new antihaemorrhoidal drug. This drug is unique. The drug is applied as a liquid to the navel and its therapeutic action is systemic. Although no results of any clinical trials have yet been published, the drug is being promoted as "the medicine proven to heal haemorrhoids". Safety is assured, but so far few patients anywhere have received the drug. Jamaica is the first country in the world to have approved the drug for general use. No local trials have been conducted and examination of local navels (by Prof R. Carpenter) suggests that only 70 % are inverted and would be suitable as a treatment reservoir. Third World countries complain of exploitation by reputable First World pharmaceutical companies. The parent company in the USA and the local manufacturers of this novel antihaemorrhoidal treatment are not well known. Drug promotion has been based more on newspaper advertisements aimed at the public than information to the medical profession. Some local practitioners have complained that their requests for information have been ignored by the local manufacturers. Jamaica has strict regulations for the licensing of new drugs in an attempt to prevent exploitation. Normally, one requirement is that the medication is approved for use not only in its country of srcin but also in many other places; however, application to the Food and Drug Administration for general use in the USA has not yet been made. Another safeguard is the existence of a committee within the Ministry of Health in Jamaica whose function is to examine the merits of new pharmaceuticals and to recommend approval (or not) of licences for new drugs. According to committee members, this committee has not been asked to consider this antihaemorrhoidal drug. When asked to comment, the Minister of Health stated that he could not recall approving the drug and that he was having difficulty obtaining the relevant file. United States IGNORANCE OF GEOGRAPHY THERE is a remote lack of geographical knowledge among school children and adults in the USA. Illiteracy is common enough but is exceeded by geographical ignorance which, in an increasingly integrated world with rapid communications, is alarming. Post office officials, telephone operators, shipping agents, and bank officials should surely have a good knowledge of geography. When materials sent to Grenada, West Indies, turn up in Granada, Spain, there is some excuse because of the coincidence of names-although it was not the president of the Costa Brava who was awarded the Nobel Peace Prize! But should not financial experts and bankers know that Sussex, England, is not in Brazil and that Bideford, Devon, is not in Saudi Arabia?, to quote just two recent examples of money transfers going astray. As physicians we are taught to ask patients whether they have travelled, but the answer may not help if we cannot distinguish Finland from Thailand or Angola from Antigua. It is even more necessary now that we remember geographical differences in disease. The incubation period for some infectious diseases is now much longer than the time spent in air travel. There are many good reasons why geography should be well taught in all schools.
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