Volume 165 Issue 3

Error rates in Australian chemical pathology laboratories Mounira Khoury, Leslie Burnett and Mark A Mackay MJA 1996; 165: 128-130 For editorial comment, see Bryant Readers may print a single copy for personal use. No further reproduction or distribution of the articles in whole or in part should proceed without the permission of the publisher. For copyright permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Abstract - Introduction - Methods - Measurement criteria - Participants - Survey - Statistical analysis - Results - Participation - Transcription errors - Analytical performance - Combined error rates - Discussion - Acknowledgements - References - Authors' details Register to be notified of new articles by email - - ©MJA1996 Abstract Objective: To measure transcription and analytical errors made by Australian chemical pathology laboratories. Design: Retrospective data collection covering the period 1 November 1993 to 1 April 1994. Setting and participants: Fourteen pathology laboratories in five Australian States (seven in the public sector, and seven in the private sector). Main outcome measures: Error rates in transcribing information from request forms to computer record systems, and laboratory performance on chemical analysis. Results: Pathology laboratories had a transcription-error rate of up to 39% and an error rate of up to 26% for analytical results. The worst-performing laboratory had errors (of patient identification or results of analysis) in 46% of requests. The three best-performing laboratories achieved 85% error-free reporting, with one achieving 95%. Conclusions: Error rates in Australian pathology laboratories vary widely, but may be as high as 46% for all specimens in some laboratories. The types of errors reported were under the control of the laboratory, and would affect the accuracy of reported pathology test results, with potential adverse outcomes for patient care and inefficient use of health-care resources. There is a need to establish broader quality assurance programs and performance requirements to reduce these types of error. MJA 1996; 165: 128-130 Introduction T he Quality in Australian Health Care Study 1 described an unacceptable rate of preventable adverse events involving patients which occur in Australian hospitals. Errors introduced into the process of requesting pathology tests can adversely affect patient management and will detract from quality of care and services. 2 At best, a sample may need to be collected again to repeat the analysis, inconveniencing the patient, delaying treatment and increasing the cost. At worst, a doctor may act on incorrect results and the patient may be treated inappropriately. In its most common diagnostic setting, the process of requesting pathology tests seems simple: the doctor writes a request, the pathology laboratory interprets the request, transcribes information from the request form to its computer system, performs the analysis, and the pathologist produces a printed report for return to the doctor. This process assumes that the patient has been correctly identified, an appropriate specimen has been obtained, analysis has been correctly performed, and the results of analysis have been communicated to the original requesting practitioner. We recently examined the accuracy of one part of the process of obtaining pathology test results in a hospital environment and found that the address of the referring doctor had been incorrectly recorded on 3% of all printed reports issued, delaying or preventing delivery of the final pathology report. 3 If this rate of error were typical for the many other steps of the requesting process for pathology tests, then the total error rate in obtaining results would be extremely high. To address this question, we surveyed clinical pathology laboratories from both public and private sectors of five Australian States to determine whether error rates in pathology are as widespread and as clinically significant as our earlier study suggested. Methods Measurement criteria We identified potential indicators using national Quality Award criteria for benchmarking indicators, 4 focusing on factors affecting medical outcomes which arose from the pathology laboratory. In this paper, we report on transcription errors and analytical performance in chemical pathology quality assurance programs. Details of these criteria and how they were measured are shown in Box 1. We did not examine how laboratories functioned to deliver these outcomes. Participants We approached 18 large National Association of Testing Authorities-registered laboratories, well recognised in the industry, representing both public and private sectors, in five Australian States (Queensland, New South Wales, Victoria, Tasmania and South Australia). Survey Survey forms, which included detailed instructions and operational defini tions of the information required, were completed by the laboratories between 1 May and 31 July 1994. One hundred hand-written pathology request forms dated between 1 November 1993 and 1 April 1994 were randomly selected by the participating laboratories. We excluded request forms which also contained requests for blood transfusion or tissue pathology because some laboratories adopt more stringent identification criteria for these types of specimens. Laboratories scored the number of transcription errors (defined as any instances where the data on individual request forms were not identical to the data entered into the laboratory's computer system 5 ). Chemical pathology quality assurance (QA) data were from one cycle of analysis within the QA program (there are two or three cycles annually, depending on the program) during 1993 and 1994. Laboratories scored the total number of QA samples analysed, and the proportion of results of these analyses that lay outside the allowable limits of error of the QA program. All data, as well as a summary of the relative performance of all other participants (each assigned a number so that they were not identifiable), were returned to each laboratory for validation before final analysis. Statistical analysis Data analysis was based on the binomial distribution. 5 Calculation of combined error rates was based on the product of constituent error-free components, with the standard deviation calculated from the sum of variances of individual component errors. Results Participation Fourteen laboratories (seven public and seven private, numbered 1-14 to preserve anonymity) completed the entire benchmarking study; all five States were represented. Transcription errors Box 2 shows our findings for particular types of transcription errors. Most laboratories lay within a tight distribution clustered around median error rates of 1% to 3%. For each transcription error listed, a single outlier -- a different laboratory in each case -- performed particularly badly. The Figure shows that, while two laboratories were able to achieve overall transcription-error rates of less than 3%, four had error rates more than two standard deviations above the mean error rate (13%) of participating laboratories ( P < 0.05). The laboratory with the poorest performance reported a transcription-error rate of 39%. Analytical performance Laboratories recorded errors outside the allowable limits of error in up to 26% of analytical results. As shown in the Figure, four laboratories reported unacceptable performance more than two standard deviations above the mean rate (11.4%) of participating laboratories ( P < 0.05). Combined error rates By matching the transcription-error rate with analytical performance, we were able to measure the proportion of all pathology requests that would have been free of either type of error (Figure). Three laboratories showed superior performance compared with peers, achieving 85% error-free reporting, with one achieving 95% error-free reporting (a total error rate of less than 5%). These three laboratories represented both the public and private sectors, were all from different States, and each used a different computer system and clinical chemistry analyser. The two laboratories which showed the poorest performance reported transcription errors or unacceptable ana lytical performance in more than a third of all requests. They were both hospital laboratories from the same State. Their high total error rates were particularly influenced by transcription errors. Discussion This pilot survey of laboratory performance is the first of its kind to have been done in Australia. Previous studies have reported particular types of laboratory errors (e.g., patient ward location or address) in 0.08% 6 to 3% 3,6,7 of requests. We have confirmed that median error rates for individual types of errors in routine pathology requests are of the order of 3% 3 (see Box 2), and overall error rates can be as high as 46%. While some of the laboratories operated with few or no errors, eight of the fourteen reported significantly inferior performance (Figure). Further, our findings indicate that some laboratories may be making transcription errors in up to 39% of all request forms, and can have error rates of 9% in patient identification data and 17% in data such as sex and date-of-birth. Such error rates should be a cause of clinical concern. Risk management in pathology laboratories recognises the relationship between proper identification of specimens and the prevention of adverse patient-care-related incidents. 2 Our study was not designed to trace particular errors to final clinical outcomes, or to distinguish between errors on the basis of severity. However, it would be surprising if transcription-error rates of the magnitude we encountered did not contribute to adverse clinical outcomes. Are the errors caused by the requesting doctor, or by the laboratory? Several laboratories used direct electronic capture of patient data from a database, which should minimise errors in patient identification data arising from illegible handwriting. These laboratories did not have lower rates of transcription error for patient identification data than those relying solely on handwritten pathology requests. Indeed, the two laboratories with the highest overall rates of transcription error both obtained their patient identification data from a central database. This leads us to conclude that poor handwriting by the requesting doctor was not the major factor in high rates of transcription errors. Errors in pathological tests come at a considerable cost to the community. Expenditure on pathology investigations in Australia amounts to some $1.4 billion -- approximately 4% of total health services expenditure (Australian Association of Pathology Practices, personal communication). Incorrect tests being performed in up to 15% of cases wastes medical resources. Requesting doctors being incorrectly identified on up to 17% of requests will result in laboratories incurring unnecessary delivery costs and doctors incurring additional costs, as they will need to obtain duplicate copies of reports not delivered, and will request repeat testing for results unable to be located. We believe that most of these errors could have been prevented by the laboratories. The three best-performing laboratories in our study used different equipment and computer systems, and operated in both public and private sector environments. We therefore suggest that superior overall performance can be achieved by controlling error rates at each step in the process, and that this can be done in diverse ways. All recognised medical testing laboratories within Australia are required to be accredited, and to participate in QA programs for analytical quality. However, there are no minimum standards of performance which laboratories are required to maintain within these QA programs. There are also no Australian QA programs which monitor non-analytical aspects of pathology laboratories, such as transcription errors. We recommend that QA programs should be introduced for a range of clinically important areas of laboratory performance, such as request transcription accuracy, transport and analysis times for key analytes (e.g., potassium), rapid reporting of critical patient data, and client satisfaction, in addition to existing programs for analytical quality. We also recommend that summaries of actual and achievable performance in these QA programs be published. Without laboratory participation and satisfactory performance in such programs, doctors cannot be confident that test results are correct. Indeed, they cannot even be confident that the result was obtained for the correct patient. Lower error rates in pathology tests should lead to improved patient outcomes and less wastage of health resources. Acknowledgements We thank the staff of the participating laboratories for their assistance with this study. We are grateful to Elizabeth Benson, Jon Currie, Jeremy Chapman, Doug Chesher and Ruth Pojer for their critical comments on the manuscript. References Wilson RM, Runciman WB, Gibberd RW, et al. The Quality in Australian Health Care Study. Med J Aust 1995; 163: 458-471. Lord JT. Risk management in pathology and laboratory medicine. Arch Pathol Lab Med 1990; 114: 1164-1167. Banning J, Brown J, Hooper L, et al. Reduction of errors in laboratory test reports using continuous quality improvement (CQI) techniques. Clin Lab Management Rev 1993; 7: 424-437. Australian Quality Awards Foundation. Assessment criteria and application guidelines. Sydney: Australian Quality Council, 1994. Grant EL, Leavenworth RS. Statistical quality control. 6th ed. Singapore: McGraw-Hill. 1988. Burnett L, Banning J. Reduction of errors in laboratory test reports: comparison of continuous quality improvement techniques with laboratory information system techniques. In: Parkany M, editor. Quality assurance and TQM for analytical laboratories. Cambridge, UK: The Royal Society of Chemistry, 1995: 97-101. Chambers AM, Elder J, O'Reilly DStJ. Blunder-rate in a clinical biochemistry service. Ann Clin Biochem 1986; 23: 470-473. (Received 20 Nov 1995, accepted 22 May 1996) Authors' details Faculty of Clinical Chemistry, School of Life Sciences, University of Technology (Gore Hill Campus), Sydney, NSW. Mounira Khoury, MSc(Clin Biochem), Graduate Student. Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, NSW. Leslie Burnett, PhD, FRCPA, Director of Clinical Chemistry. Mark A Mackay, MSc, Hospital Scientist and Quality Facilitator. Reprints: Associate Professor Leslie Burnett, Assistant Director, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW 2145. < URL: http://www.mja.com.au/> © 1996 Medical Journal of Australia.

Mounira Khoury · Leslie Burnett · Mark A Mackay

Is a general practitioner legally bound to render assistance to a stranger? Paul Gerber The finding that a general practitioner has a duty to attend any person in a medical emergency, in the absence of any previous professional relationship, is brand new law MJA1996; 165: 159-161 Readers may print a single copy for personal use. No further reproduction or distribution of the articles in whole or in part should proceed without the permission of the publisher. For copyright permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Register to be notified of new articles by email - - ©MJA 1996 The case of Woods v. Lowns and Procopis (decision of the Court of Appeal of NSW, handed down 5 February 1996: unpublished to date) is likely to have wide implications for the future practice of medicine in Australia. The trial involved two main issues: (i) should judges decide cases of medical negligence by acting on unproven scientific evidence contrary to the weight of expert medical opinion; and (ii) is there a legal obligation upon a general practitioner to attend a person with whom he or she has no professional relationship? I have dealt in the Journal with the first aspect of the case, 1 involving Dr Procopis. I was highly critical of the trial judge's finding against this specialist, concluding that his Honour had misconceived his role, and predicting that the "Procopis" component of his judgment would be reversed on appeal. My analysis did not meet with universal approval. 2 My criticism of the judge's handling of the evidence against Dr Procopis proved justified -- the verdict against the specialist was set aside on appeal. A majority of the Court of Appeal of the Supreme Court of New South Wales held that, while it is for the courts to decide the content of the duty of care which a medical specialist owes to a patient, it does not follow that a judge "will simply or readily put aside the considered judgment and/or experience of those skilled in the field and their opinion of what the care of the patient warranted" ( Woods v. Lowns and Procopis on appeal ). This concession has come some way toward attenuating the more extreme view generally ascribed to the decision in Rogers v. Whitaker 3 (i.e., that, generally speaking, the answer to the question whether the patient has been given all the relevant information to choose between undergoing and not undergoing the proposed treatment does not depend on medical standards or practice). Here I deal with the case against Dr Lowns, the general practitioner, who, at first instance, was held liable in negligence for failing to attend the plaintiff when allegedly requested to do so. The finding against him was upheld by majority of the Court of Appeal of the Supreme Court of New South Wales (Kirby P and Coles JA), who concluded that Dr Lowns, albeit a stranger to the plaintiff, was nevertheless liable for the unfortunate medical misadventure which resulted in the case, all said to be attributable to Dr Lowns' failure to attend the plaintiff at his home when requested to do so. The plaintiff, a boy aged ten years at the time, had a history of epilepsy and suffered an attack of status epilepticus in 1987 while on vacation with his family. Briefly, the relevant facts, taken from the trial judge's findings, were these: when the boy's mother -- after some considerable delay -- discovered that her son was fitting, she directed her older son "to go for an ambulance", and told her daughter (then nearly 15 years of age) "to go and get a doctor". The girl insisted that she went to Dr Lowns' surgery and spoke "to a man who answered the door". She claimed that she told that man that her mother had sent her because her brother was having a bad fit, that they had called for an ambulance, and "that we needed a doctor and could he come up?". The girl identified this man in Court as Dr Lowns, and claimed that he had refused to come, telling her instead to bring her brother to the surgery. By the time the ambulance arrived and took the boy to another medical practice (where he was injected with diazepam) and then to hospital (still fitting), he had suffered severe brain damage. The boy sued both Dr Procopis and Dr Lowns (as well as the two doctors who injected him with diazepam, a claim later withdrawn). At first instance, both Dr Procopis and Dr Lowns were found to have been negligent: Dr Procopis for having failed to instruct the parents in the use of rectal diazepam, and Dr Lowns for failing to attend the plaintiff at his home. At the trial, Dr Lowns denied that the girl had ever been to his surgery. His case was that the alleged conversation had never occurred. However, he made a number of fatal concessions: (i) that if he had been requested to attend the boy, he would -- and should -- have gone, (ii) that if he had attended the boy, he would have injected him with diazepam, and (iii) that if the boy had been treated at that point in time, it is probable that the tragic consequences would have been avoided. The identification of Dr Lowns by the boy's sister must be treated with considerable scepticism: she alleged that Dr Lowns was smoking a pipe (he does not), and there is little doubt that the doctor is not easily recognisable from her initial description of him. For good measure, the girl's ex- planations of these discrepancies lack conviction. This notwithstanding, the judge chose to believe her and rejected Dr Lowns' denial. (This finding was not challenged on appeal.) In the result, the judge entered a verdict in favour of the plaintiff in excess of $3 million. The finding that a general practitioner has a duty to attend any person in a medical emergency, in the absence of any previous professional relationship, is brand new law. With a stroke of a pen, the Court "discovered" a duty which did not previously exist. The origin of this so-called duty is found in the seminal speeches in Donoghue v. Stevenson, 4 where a majority of the House of Lords held, some 60 years ago, that a soft-drink manufacturer was liable in negligence to a plaintiff who claimed to have suffered an attack of gastroenteritis as a result of drinking the defendant's ginger beer (alleged to have contained the decomposed remnants of a snail). This case discovered the "neighbour" principle, "based upon a general public sentiment of moral wrongdoing for which the offender must pay" (per Lord Atkin, at p 580). 4 This "general public sentiment", excavated from the Old Testament, commanding that you are to love your neighbour, has mutated into law that you must not "injure" your neighbour. The legal question "who is my neighbour?" receives the restricted reply "persons so closely and directly affected by my act that I ought reasonably to have them in contemplation as being so affected when I am directing my mind to the acts and omissions which are called in question" (per Lord Atkin, at p 580). 4 This "neighbour" principle had never previously been applied to doctor and stranger. Indeed, the trial judge himself (in Woods v. Lowns and Procopis ) noted: Something other than the foreseeability of harm is required before the law imposes a duty to intervene. It has been held in other common law jurisdictions that a doctor is under no duty to attend upon a person who is sick, even in an emergency, if that person is one to whom the doctor has not and never has been in a professional relationship of doctor and patient: see Jones, Medical Negligence , Sweet and Maxwell 1991 at p 24, par 2.21; Kennedy & Grubb, Medical Law , Butterworths (2nd ed) 1994 at p 79. His Honour cited a number of United States decisions, all of which held, firstly, that there can be no liability to attend to members of the public and, secondly, that there can be no negligence unless and until the relationship of doctor and patient has been established. How, then, did the majority impose this hitherto unknown legal obligation? The answer is that their Honours confused a moral duty with a legal one. The Medical Practitioners Act 1938 (NSW) s 27 (1) (now re-enacted in s 37 of the Medical Practice Act 1992 [NSW]) does state that "professional misconduct" in a registered medical practitioner is, inter alia: (h) refusing or failing, without reasonable cause, to attend, within a reasonable time after being requested to do so, on a person for the purpose of rendering professional services in the capacity of a registered medical practitioner in any case where the practitioner has reasonable cause to believe that the person is in need of urgent attention by a registered medical practitioner. However, while the legislation describes the contents of professional misconduct which will attract professional sanction, there is nothing in the Act which imposes a statutory obligation to attend a stranger, and it would be quite wrong to elevate "professional misconduct" to a breach of statutory duty, thus giving rise to an independent cause of action. It follows that those who maintain that the decision in Woods v. Lowns and Procopis is relevant only to medical practitioners in New South Wales are on shaky ground. I believe that, on appeal, only the dissenting judge (Mahoney AJ) correctly summarised the position when he stated: "We are concerned with whether the moral obligation to which (as I assume) the doctor was subject should be a legal obligation" ( Woods v. Lowns and Procopis, at p 13). His Honour noted that: Counsel have not been able to find any case in support of the present existence of such an obligation. Nor has any member of the Court. No case has been put to the contrary. I am conscious of the fiction that what the law creates has always been the law. But the implications of this case are great. . . . In this, as in other areas of law, the Court now faces squarely the nature of its decision: it prefers reality to fiction. Therefore, it is not inappropriate that I describe what the Court is here asked to do is imposing a legal obligation which presently does not exist ( Woods v. Lowns and Procopis, at p 15). I suggest that both the trial judge (Badgery-Parker J) and the majority of the Court of Appeal of the Supreme Court of NSW have not only "discovered" a relationship of proximity between doctor and stranger hitherto unknown to the law, but that they were wrong to hold that a doctor is under a legal duty to attend a person with whom he or she has had no previous professional relationship, a duty said to be based on the "proximity" or "neighbour" test, so that the only remaining question was whether the damage in suit was reasonably foreseeable if a doctor, otherwise in a position to do so, refused to render medical assistance. I submit that this is not only bad law; it is a blatant usurpation by the Court of what is solely the function of Parliament. If the Legislature wants to impose such a duty, so be it. It is not the business of judges to do so. While this is not the place to examine the history and development of the law of negligence, it is with no disrespect to the majority of the Court of Appeal to say that in the case Woods v. Lowns and Procopis Homer nodded,* and that the majority's reasoning was simplistic. It has long been held that the tort of negligence does not include -- save in a special relationship -- an obligation of rescue. The claim against Dr Lowns was argued in negligence and only in negligence; no breach of any other civil obligation was, or could have been, demonstrated. The answer to the plaintiff's claim must surely be that the tort of negligence does not extend to a failure by a doctor to attend a stranger. If there is such a duty, it must be sought elsewhere and, in this area, none of the cases to date have ever suggested that a person having goods or skill must provide them for the benefit of another. In this case, the majority sought to make a great deal of Dr Lowns' concession that, had he been requested to do so, he would and should have attended the plaintiff. The doctor went further, admitting in cross-examination that he could well foresee harm to a fitting child if he did not attend immediately and administer treatment. But that concession could not amount to an admission that he was under a legal obligation to attend the plaintiff, as the majority appear to have thought. After Dr Lowns indicated that he would seek special leave to appeal the decision to the High Court of Australia, the parties settled their claim. The medical profession is thus deprived of obtaining a more definitive pronouncement on a controversial decision in which, in my opinion, the majority of the New South Wales Court of Appeal came to a wrong conclusion, "bending" the law to reach a socially compelling result. References Gerber P. Has informed consent become a legal nightmare? Med J Aust 1995; 163: 262-264. Bates PW. Social and legal changes in medical malpractice litigation. Med J Aust 1995; 163: 264-268. Rogers v. Whitaker (1992) 175 CLR 479. Donoghue v. Stevenson [1932] AC 562 . Author's details 6 Devaney Lane, Corinda, QLD 4075. Paul Gerber, LLB, DJur, Adjunct Professor of Law, University of New South Wales. < URL: http://www.mja.com.au/> © 1996 Medical Journal of Australia.

Paul Gerber

Oral retinoids and pregnancy Annabelle Chan, Marshall Hanna, Malcolm Abbott and Rosemary J Keane MJA1996; 165: 164-167 Readers may print a single copy for personal use. No further reproduction or distribution of the articles in whole or in part should proceed without the permission of the publisher. For copyright permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Introduction - Adverse reactions - Teratogenicity - Prescribing guidelines - Compliance - Pregnancy prevention programs - Recommendations - Conclusions - Acknowledgements - References - Authors' details Register to be notified of new articles by email - - ©MJA 1996 The oral retinoids isotretinoin and etretinate are uniquely effective in the treatment of severe cystic acne and keratinisation disorders. Because of their known teratogenicity, there are strict prescription guidelines, but exposure during pregnancy still occurs. A dedicated effort by women and their clinicians is required, involving patient selection, education and informed consent, detailed contraceptive counselling, and careful monitoring and management, including pregnancy testing before commencement of therapy. (MJA 1996; 165: 164-167) Introduction T he Australian Drug Evaluation Committee lists only five drugs in Medicines in pregnancy 1 as Category X -- drugs that have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy. The oral retinoids isotretinoin (Roaccutane, Roche) and etretinate (Tigason, Roche) are two of the five listed. The newly released acitretin (Neotigason, Roche) should also be included. These synthetic retinoids closely resemble naturally occurring vitamin A, essential for the maintenance of visual and reproductive function and for proliferation and differentiation of epithelial tissues. 2 They were released in the United States and Europe in 1982 and in Australia towards the end of 1985. Acitretin was released in Australia in late 1995 to replace etretinate, as it is more rapidly eliminated from the body. Isotretinoin is uniquely effective in severe cystic acne, and etretinate and acitretin in severe psoriasis and other keratinisation disorders which have proved recalcitrant to all other therapies. This accounts for their availability on prescription despite their teratogenicity . Adverse reactions The commonly reported adverse reactions (which are largely dose-related, of early onset and reversible on discontinuation) include dryness of the lips, mouth and eyes, hair loss and pruritus. 3 Less common but more severe, probably idiosyncratic, reactions (which may occur after weeks or months of therapy) include altered vision, headache, joint and muscle pain, abnormally raised serum transaminase levels, serum lipid changes, as well as increases in serum triglyceride and chol esterol levels and an increase in low density : high density lipoprotein ratio. Rare reactions include mental depression, severe hepatitis, diffuse hyperostosis of the spine and benign intracranial hypertension. Teratogenicity The most serious side effect, teratogenicity, was foreshadowed by animal studies, so that, at the time the drugs were released, strong warnings against exposure during pregnancy were given. The retinoids are believed to interfere with the activity and migration of cranial neural crest cells during development and thus cause craniofacial, thymic, conotrun cal heart and central nervous system malformations 4,5 (Box 1). Intellectual deficits in more than half the children exposed in utero have also been reported in follow-up studies to five years of age. 6 Isotretinoin Any fetal exposure during the first trimester within the therapeutic dose range of isotretinoin may be teratogenic. 7 Isotretinoin has a short elimination half-life of about 20 hours and the recommended contraception period after cessation of therapy is one month. Estimates from prospectively reported (i.e., before outcome was known) exposed pregnancies place the risk of teratogenicity for isotretinoin for first trimester exposure at around 28%, 7 reducing to around 4% for pregnancies occurring within one month of cessation of treatment 8 (Box 2). Etretinate Birth defects associated with etretinate include meningomyelocele, craniofacial and skeletal abnormalities and brain defects. 4,5 Etretinate is readily taken up into adipose tissue and slowly released from it. Thus, it has a long elimination half-life (120 days or more 2 ) and the recommended contraception period after therapy is two years. The best estimate from the literature of the risk of teratogenicity for exposure to etretinate during pregnancy is about 26%, 9 but the risk is likely to be less, as the pregnancies considered probably include retrospectively reported ones (in which there is a tendency to under-report normal outcomes). The risk for pregnancies occurring within two years of cessation of treatment appears to be considerably less, about 2%. All estimates are based on relatively few pregnancies (Box 2). Acitretin In spite of a shorter elimination half-life of 50 hours, a two-year contraception period after therapy has also been recommended for acitretin, as in some women there is conversion of acitretin to etretinate during therapy. 2,3,9 Up to 1994, there had been no exposures to acitretin during pregnancy reported prospectively to the manufacturer (Roche) with known outcomes; of three reported retrospectively, one aborted fetus had characteristic defects, one baby had high frequency hearing loss and a third was normal. None of the 32 prospectively reported pregnancies conceived in the two-year period after therapy has resulted in an infant with a birth defect (S Weber, Roche Products Medical Information Department, personal communication). Prescribing guidelines In Australia, authority to prescribe oral retinoids for specified conditions needs to be obtained under the Pharmaceutical Benefits Scheme, and they can only be prescribed by dermatologists (except in regions where there is no derm atologist available and a specialist physician may have authority to prescribe under State law). However, in the United States and Canada, 10 general practitioners and physicians may also prescribe these drugs. Roche recommends that: The possibility of pregnancy must be ruled out by a pregnancy test within two weeks before commencing treatment. Treatment should be commenced on the second or third day of the next normal menstrual period. An effective form of contraception should be used for at least one month before treatment, during treatment and for at least one month after cessation of treatment with isotretinoin, and for two years after treatment with etretinate and acitretin. Women should be effectively counselled about the risks to a fetus, and if pregnancy does occur they should immediately stop taking the drug and seek medical advice. To increase understanding of the implications of treatment, a specially designed consent form should be signed by the patient before commencing treatment. Breastfeeding should not occur while a woman is taking oral retinoids. The drugs should not be given to others, and should be kept out of reach of children. The manufacturer has also made available to dermatologists patient information pamphlets (also in several languages other than English), contraceptive guidelines and a special consent form for treatment. A warning that the product causes birth defects is carried on the drug package as well as the dispensed product. The Australasian College of Der matologists has provided comprehensive guidelines for prescription, focusing on signed informed consent for treatment, the performance of tests for pregnancy, liver function and lipid levels before treatment, and the importance of regular review. Compliance Despite these measures, exposure to the drugs during pregnancy has occurred both in Australia 11,12 and in other countries. While most women have been advised of the teratogenicity of the drugs, there has been less strict compliance with pregnancy tests and signed consent before initiation of treatment, with 4% of dermatologists in the Netherlands, 13 73% in the United States 14 and 80% in Australia 11 undertaking pregnancy tests, and 59% in the United States 14 obtaining signed consent for therapy. About a third of the women in the United States and Canada with exposure during pregnancy were already pregnant at the time therapy was commenced; 4,7 33% in one study 4 and 40% in the other 7 were not using contraception, while 26% were using less reliable methods and 65% of those taking oral contraception reported using contraception irregularly. 7 Women under 25 years showed the poorest compliance (50%) with contraceptive use. 7 Use of oral retinoids for other than the specified indications has been reported, 13,14 as well as prescription by unauthorised doctors, 12 and use of drugs left over from previous prescriptions or obtained from friends or relatives. 7 Pregnancy prevention programs Pregnancy prevention programs 15,16 instituted in 1988 by the manufacturer and the US Food and Drug Administration included additional features such as a check list of selection criteria for suitable patients, a self-evaluation test for patients, drug packages with drawings of associated birth defects and "avoid pregnancy" icons, a contraception referral program with reimbursement for the first visit by the manufacturer, a recommendation to use two forms of contraception simultaneously, 16 and periodic communications with prescribers and pharmacists. Encouraging outcomes were achieved among participants, such as a low pregnancy rate of 3.4 per 1000 courses of treatment with isotretinoin, 15 and a trend towards more appropriate use of contraception among women who were counselled with the entire program. 16 Even so, compliance with the guidelines, such as pregnancy testing (64% 15 ), waiting until the next menstrual period before commencing therapy (70% 15 ) and use of effective contraception, was still incomplete. Recommendations While the search continues for safer drugs, how can we reduce the risk of pregnancy in women taking oral retinoids while achieving maximum benefits from this unique group of drugs? (see Box 3). Conclusions A recent study 20 has provided further support for the teratogenicity of preformed vitamin A in dosages of 10 000 IU or more daily in the form of supplements. The recommended daily amount of vitamin A for women in Australia is 2500 IU and supplements exceeding this or heavy consumption of liver and liver products 2 should be avoided, particularly during therapy with oral retinoids, as well as during pregnancy. The successful implementation of a pregnancy prevention program during oral retinoid therapy could be viewed as a pregnancy rate no greater than the failure rate of the recommended contraceptive method. If this is taken as 0.3 per 100 woman-years for the combined oral contraceptive pill 18 (with the potential to be less with the simultaneous use of another method), then the pregnancy rate during therapy with isotretinoin, with an average contraception period of six months per woman per course (four months for treatment 11 and one month before and after therapy), ideally should not exceed 1.5 per 1000 courses of treatment. The estimated rates of 3.1 terminations per 1000 courses of treatment with isotretinoin 12 and 3.4 pregnancies per 1000 courses of treatment 15 recently reported are relatively low but can be reduced further. This requires the wholehearted commitment of women and their clinicians. Acknowledgements We are grateful to the staff of the South Australian Health Commission Library for helping us to obtain the references and many others not listed, and to Roche Products Medical Information Department for additional references and statistics on exposed pregnancies. References Australian Drug Evaluation Committee. Medicines in pregnancy. An Australian categorisation of risk of drug use in pregnancy. 2nd ed. Canberra: AGPS, 1992. Chalmers RJG. Retinoid therapy -- a real hazard for the developing embryo. Br J Obstet Gynaecol 1992; 99: 276-278. Saurat J-H. Side effects of systemic retinoids and their clinical management. J Am Acad Dermatol 1992; 27: S23-S28. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313: 837-841. Rosa FW, Wilk AL, Kelsey FO. Teratogen update: vitamin A congeners. Teratology 1986; 33: 355-364. Teratology Society: recommendations for isotretinoin use in women of childbearing potential. Teratology 1991; 44: 1-6. Dai WS, LaBraico JM, Stern RS. Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol 1992; 26: 599-606. Dai WS, Hsu M-A, Itri LM. Safety of pregnancy after discontinuation of isotretinoin. Arch Dermatol 1989; 125: 362-365. Geiger J-M, Baudin M, Saurat J-H. Teratogenic risk with etretinate and acitretin treatment. Dermatology 1994; 189: 109-116. Hogan DJ, Strand LM, Lane PR. Isotretinoin therapy for acne: a population-based study. Can Med Assoc J 1988; 138: 47-50. Lee M, Cooper A. Survey of Australian isotretinoin prescribing. Australas J Dermatol 1991; 32: 13-16. Chan A, Keane RJ, Hanna M, Abbott M. Terminations of pregnancy for exposure to oral retinoids in South Australia, 1985-1993. Aust N Z J Obstet Gynaecol 1995; 35: 422-426. Eurocat. Surveillance of the retinoic acid embryopathy: a pharmacy based study. Eurocat Newsletter December 1992; 6(4). Doering PL, Araujo OE, Frohnapple DJ, et al. Patterns of prescribing isotretinoin: focus on women of childbearing potential. Am Pharmacother 1992; 26: 155-161. Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-prevention program in women of childbearing age receiving isotretinoin. N Engl J Med 1995; 333: 101-106. Pastuszak A, Koren G, Rieder MJ. Use of the retinoid pregnancy prevention program in Canada: patterns of contraception use in women treated with isotretinoin and etretinate. Reprod Toxicol 1994; 8: 63-68. Kovacs G. Oral contraceptives -- can we make them more effective? Med J Aust 1993; 159: 224-225. Ceyrac DL, Serfaty D, Lefrancg H. Retinoids and contraception. Dermatology 1992; 184: 161-170. Sturkenboom MCJM, de Jong-van den Berg LTW, van Voorst-Vader PC, et al. Inability to detect plasma etretinate and acitretin is a poor predictor of the absence of these teratogens in tissue after stopping acitretin treatment. Br J Clin Pharmacol 1994; 38: 229-235. Rothman K, Moore LL, Singer MR, et al. Teratogenicity of high vitamin A intake. N Engl J Med 1995; 333: 1369-1373. Authors' details South Australian Health Commission, Public and Environmental Health Service, Adelaide, SA. Annabelle Chan, FAFPHM, Senior Medical Consultant, Pregnancy Outcome Unit; and South Australian Birth Defects Register, Women's and Children's Hospital, North Adelaide, SA. Malcolm Abbott, AUA, FSHP, Pharmacist, Therapeutic Goods Section; currently Rural Pharmacist, Territory Health Services, Katherine District, NT. Rosemary J Keane, RN, RM, Midwife, Pregnancy Outcome Unit. Flinders Medical Centre, Adelaide, SA. Marshall Hanna, FRACP, FACD, Senior Visiting Dermatologist, Department of Dermatology. Reprints and Correspondence: Dr A Chan, South Australian Health Commission, Public and Environmental Health Service, PO Box 6, Rundle Mall, Adelaide, SA 5000. To top of article ©MJA 1996 < URL: http://www.mja.com.au/> © 1996 Medical Journal of Australia.

Annabelle Chan · Marshall Hanna · Malcolm Abbott · Rosemary J Keane