Consensus statements

The need for consistency in assessing international medical graduates for work in Australia led the Council of Australian Governments, in 2006, to direct health ministers to implement a nationally consistent approach. An Implementation Committee was established in late 2006 to oversee the development of the new assessment process; the first steps were completed by July 2007 and further development will occur over the next 12 months. The pre-existing Australian Medical Council (AMC) examination pathway will continue to be available, and there will be two additional pathways for non-specialists. The pre-existing pathway for specialists is being revised. Elements that are being introduced include: standardised pre-employment assessment, including an off-shore screening examination; assessment of competence against a standardised position description and, if necessary, a structured clinical interview by an AMC-accredited provider before obtaining limited registration; orientation to the job, the Australian health care system and to communication and cultural issues; standardised supervision and supervisory reporting; a requirement for compulsory continuing professional development for reregistration; workplace-based assessment; assessment by an AMC-accredited provider before gaining full registration; and consistency of assessment for specialists by specialist colleges. Some elements have been operating in some jurisdictions from July 2007, and there is a commitment to full implementation in participating jurisdictions by July 2008.

on behalf of the Implementation and Technical Committees, under the auspices of the Australian Health Ministers’ Advisory Council

Paracetamol is involved in a large proportion of accidental paediatric exposures and deliberate self-poisoning cases, although subsequent hepatic failure and death are both uncommon outcomes. The optimal management of most patients with paracetamol overdose is usually straightforward. However, several differing nomograms and varying recommendations regarding potential risk factors for hepatic injury introduce complexity. In order to reconcile management advice with current Australasian clinical toxicology practice, revised guidelines have been developed by a panel of clinical toxicologists consulting to the poisons information centres in Australia and New Zealand using a workshop and consultative process. This article summarises the rationale for the recommendations made in these new guidelines.

Frank F S Daly MB BS, FACEM · John S Fountain MB ChB · Lindsay Murray MB BS, FACEM · Andis Graudins MB BS, PhD, FACEM, FACMT · Nicholas A Buckley MD, FRACP

As part of the 3E program, we conducted a systematic literature review and gathered consensus from 23 practising Australian rheumatologists to develop guidelines for early identification of ankylosing spondylitis and specialist referral. In three rounds of break-out sessions followed by discussion and voting, the specialist panel addressed three questions related to diagnosis of ankylosing spondylitis: In individuals with back pain, what are the early clinical features that suggest ankylosing spondylitis? How useful is imaging in identifying early ankylosing spondylitis? Based on which clinical features should a general practitioner refer a patient to a rheumatologist for further evaluation? The panel agreed on six recommendations related to the three questions: 1a. Early clinical features to suggest ankylosing spondylitis include inflammatory back pain and age at symptom onset < 45 years. 1b. The absence of symptomatic response to an appropriate course of non-steroidal anti-inflammatory drugs makes the diagnosis of ankylosing spondylitis less likely. 1c. Raised inflammatory markers are supportive, but their absence does not rule out the diagnosis of ankylosing spondylitis. 2a. Despite low sensitivity to detect changes of early ankylosing spondylitis, plain radiographs of the pelvis and spine are appropriate initial imaging techniques. 2b. Magnetic resonance imaging is a useful imaging modality for detecting early changes of ankylosing spondylitis. 3. Individuals with inflammatory back pain should be referred to a rheumatologist for further evaluation. Effective dissemination and implementation of these recommendations are important to standardise the approach to early diagnosis of ankylosing spondylitis.

Tracey Kain MB ChB, MPH · Jane Zochling MB BS, FRACP · Andrew Taylor MB BS, FRACP · Nicholas Manolios MB BS, FRACP · Malcolm D Smith MB BS, FRACP · Mark D Reed MB BS · Matthew A Brown MB BS, MD, FRACP · Lionel Schachna MB BS, FRACP, PhD

Perinatal care at the borderlines of viability demands a delicate balance between parents’ wishes and autonomy, biological feasibility, clinicians’ responsibilities and expectations, and the prospects of an acceptable long-term outcome — coupled with a tolerable margin of uncertainty. A multi-professional workshop with consumer involvement was held in February 2005 to agree on management of this issue in New South Wales and the Australian Capital Territory. Participants discussed and formulated consensus statements after an extensive consultation process. Consensus was reached that the “grey zone” is between 23 weeks’ and 25 weeks and 6 days’ gestation. While there is an increasing obligation to treat with increasing length of gestation, it is acceptable medical practice not to initiate intensive care during this period if parents so wish, after appropriate counselling. Poor condition at birth and the presence of serious congenital anomalies have an important influence on any decision not to initiate intensive care within the grey zone. Women at high risk of imminent delivery within the grey zone should receive appropriate and skilled counselling with the most relevant up-to-date outcome information. Management plans can thus be made before birth. Information should be simple, factual and consistent. The consensus statements developed will provide a framework to assist parents and clinicians in communication, decision making and managing these challenging situations.

Kei Lui MB BS, MD, FRACP · Barbara Bajuk MPH · Kirsty Foster MB ChB, DRCOG, MEd · Arnolda Gaston MPH · Alison Kent BM BS, FRACP · John Sinn MB BS, FRACP, MMed(Epi) · Kaye Spence RN, BEd(N), MN, FCN · Wendy Fischer BA(Hons), RN, CM · David Henderson-Smart MB BS, PhD, FRACP

The National Diabetes in Pregnancy Advisory Committee (NDIPAC) is a multidisciplinary committee established in November 2000 by the Commonwealth Department of Health and Aged Care as part of the National Diabetes Strategy. On behalf of the NDIPAC, we present the first Australian consensus statement (endorsed by the Committee in February 2004) on diabetes control for women with type 1 or type 2 diabetes who are preparing for pregnancy: Women planning pregnancy should aim to achieve a target HbA1c value of < 7% (where the upper limit of the normal range for people without diabetes is < 6%) (If the normal range for people without diabetes is specified otherwise, the target HbA1c level should be < 1% above the upper limit of normal.) The following important qualifying statements apply: Women with diabetes should aim to achieve the best control of diabetes possible in preparation for pregnancy. This should include achieving blood glucose levels as close to the normal range as possible, while avoiding hypoglycaemia. Decisions about the precise glucose level targets to be achieved should be made on an individual basis, with collaboration between the woman and her healthcare team. Women who are able to achieve better control of their diabetes than the target value indicated above (eg, an HbA1c level of 6%) should be encouraged to maintain these levels in preparation for pregnancy. Other aspects of care are also important in preparation for pregnancy. These include healthy eating, taking folic acid supplements, and detection and treatment of other diabetes-related complications. It is recommended that tighter control of blood glucose levels (eg, HbA1c < 6% or within the upper limit of the normal range) be targeted once pregnancy is achieved to minimise the risk of pregnancy complications and long-term metabolic consequences for the child. These recommendations were made after reviewing and discussing the available data (the references listed here are a selection of the data sources considered the most relevant).1-15 The recommendations have now been endorsed by the Australasian Diabetes in Pregnancy Society, the Australian Diabetes Society, the National Diabetes Strategy Group and the Royal Australasian College of General Practitioners. The NDIPAC suggests that the recommendations be used to determine action strategies for improving outcomes in pregnancies complicated by diabetes. For example, they could be applied in: designing appropriate enhanced primary-care guidelines and target HbA1c levels for women in their child-bearing years; flagging pathology results (specifically, the HbA1c value in women of child-bearing potential) for action by treating clinicians; ongoing monitoring of pre-pregnancy glycaemic control using the framework of the National Diabetes in Pregnancy Audit Program (for more information, see the Australasian Diabetes in Pregnancy Society website, www.adips.org).

on behalf of the National Diabetes in Pregnancy Advisory Committee

Gestational diabetes mellitus -- management guidelines The Australasian Diabetes in Pregnancy Society Linda Hoffman, Chris Nolan, J Dennis Wilson, Jeremy J N Oats and David Simmons MJA 1998; 169: 93-97 Synopsis - Screening - Diagnosis - Management of GDM - Patient education - Fetal surveillance - Timing of delivery - Delivery - Neonatal management - Maternal follow-up - Directions for future research - Acknowledgements - References - Authors' details - - ©MJA1998 Synopsis GDM is defined as carbohydrate intolerance of variable severity with onset or first recognition during pregnancy. Universal screening is recommended. If selective screening is considered more appropriate (because of limited resources or known low GDM incidence), screening may be reserved for those at higher risk. Risk factors include glycosuria, age over 30 years, obesity, family history of diabetes, past history of GDM or glucose intolerance, previous adverse pregnancy outcome and belonging to a high risk ethnic group. The recommended screening test for GDM is performed at 26-28 weeks' gestation and positive results are: 1 hour venous plasma glucose level ≥7.8 mmol/L after a 50 g glucose load (morning, non-fasting); or 1 hour venous plasma glucose level ≥8.0 mmol/L after a 75 g glucose load (morning, non-fasting). Confirmation of diagnosis after a positive screening test: a 75 g oral glucose tolerance test (fasting) with a venous plasma glucose level at 0 hours of ≥5.5 mmol/L and/or at 2 hours of ≥8.0 mmol/L.* Patient education is very important and a team approach, if available, is beneficial. Dietary therapy is the primary therapeutic strategy, with insulin added where required to achieve the minimum goals for glycaemic control: fasting blood glucose <5.5 mmol/L, 1 hour postprandial <8.0 mmol/L or 2 hour postprandial <7.0 mmol/L. Careful antepartum fetal surveillance is essential. Continuation of the pregnancy in uncomplicated GDM to 10 days beyond term is acceptable provided that indications from fetal monitoring are reassuring. Close neonatal monitoring is important, particularly for the detection of hypoglycaemia. Maternal follow-up, with an oral glucose tolerance test, should be performed 6-8 weeks postpartum, then at least every 2 years, because of the increased risk of developing permanent diabetes. Prospective trials are needed to clarify whether universal screening is justified, and to determine the degree of maternal hyperglycaemia that causes an adverse outcome for the offspring. The management strategies in this article have been the subject of widespread discussion with the ADIPS membership between 1991 and 1998 at annual scientific meetings, annual general meetings, and in ADIPS newsletters. They represent the majority opinion. * Cut-off point for Australia; cut-off point in New Zealand ≥9.0 mmol/L. Introduction Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance of variable severity with onset or first recognition during pregnancy.1 Women with GDM are a heterogeneous group and may include those with unrecognised pre-existing non-insulin-dependent diabetes (type 2) and also a small number with insulin-dependent diabetes. The presence of GDM has implications for both the baby and the mother. Although there is no evidence that perinatal mortality is increased in pregnancies with treated GDM, some studies have shown perinatal mortality to be increased in untreated GDM.2-4 GDM is associated with increased perinatal morbidity, the characteristics of which are the same as for infants of mothers with overt diabetes (eg, macrosomia, neonatal hypoglycaemia, hyperbilirubinaemia, respiratory distress syndrome).5 In considering longer term outcomes for the baby, evidence is gradually mounting that GDM adds an intrauterine environmental risk factor to an already increased genetic risk for the development of obesity and/or diabetes.6-8 In one follow-up study insulin therapy for GDM was associated with less adiposity in the offspring.9 For the mother, GDM is a very strong risk factor for the development of permanent diabetes later in life (49.9% with up to 28 years' follow-up).10 Screening There has been much debate about whether universal or selective screening of pregnant women for GDM is more appropriate.11-13 Moses and Colagiuri recently estimated that, between 1991 and 1994, 50% of pregnant women in New South Wales were not screened for gestational diabetes.14The Australasian Diabetes in Pregnancy Society (ADIPS) recommends that screening for GDM should be considered in all pregnant women. However, if resources are limited, screening may be reserved for those at highest risk. Risk factors include: Glycosuria; Age over 30 years; Obesity; Family history of diabetes; Past history of GDM or glucose intolerance; Previous adverse pregnancy outcome; and Belonging to an ethnic group with a high risk for GDM. Ethnicity is a particularly important factor determining incidence of GDM (eg, very high risk -- Australian Indigenous, Polynesian and South Asian [Indian] groups; moderate high risk -- Middle Eastern and other Asian groups).15 Most Australian centres report a GDM incidence of 5.5%-8.8%.16-19 When selective screening is deemed more appropriate because of known low GDM incidence, the ADIPS criteria are similar to those recommended by the American "Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus".20 A recent article by Naylor et al21 derived a risk factor scoring system that excluded the need for screening up to a third of pregnant women. However, complex criteria for selective screening may cause difficulties in busy clinical practice. A summary of the screening and diagnostic procedures recommended by ADIPS is given in the Table. Diagnosis The guidelines for diagnosing GDM in Australia are essentially unchanged from those recommended for use in Australasia in 1991.22 Although there are no uniform international criteria for the diagnosis of GDM, commonly used criteria are those of O'Sullivan and Mahan23 and the World Health Organization (WHO).24 One problem with the development of absolute diagnostic criteria is the lack of evidence that perinatal mortality is increased in pregnancies associated with mild degrees of hyperglycaemia. The commonly used diagnostic criteria were not formulated to assess the risk of adverse perinatal outcomes, although this was a factor taken into account in the diagnostic criteria at the Mercy Hospital for Women, Melbourne.4 The existence of different methods of performing glucose tolerance tests has also hindered the development of uniform diagnostic criteria for GDM. After consensus, ADIPS has endorsed the diagnostic criteria developed by the working party chaired by Dr F I R Martin in 1991, which are modified WHO criteria.22 In New Zealand, the 2 hour oral glucose tolerance test (OGTT) cut-off value for a positive diagnosis is a venous plasma glucose level of 9.0 mmol/L. This figure was chosen by a majority decision of specialists at the 1992 meeting of the New Zealand Society for the Study of Diabetes. They chose the higher figure to reduce the worry and inconvenience for women of being given a false positive diagnosis and to reduce the strain on stretched specialist resources in many centres. ADIPS recognises the importance of working towards an Australasian consensus on this issue. If the clinical suspicion of GDM is high, a diagnostic OGTT is indicated, irrespective of the stage of pregnancy. In such circumstances, if an OGTT gives normal results early in pregnancy the test should be repeated between 26 and 30 weeks' gestation. A 75 g OGTT should use 75 g of anhydrous glucose or the equivalent, and preferably should also be performed after a high carbohydrate diet of at least 150 g of carbohydrate for three days. Management of GDM A team approach is ideal for managing women with GDM and, if available, should be used. The team would usually comprise an obstetrician, diabetes physician, a diabetes educator (diabetes midwifery educator), dietitian, midwife and paediatrician. In practice, however, the team approach is not always possible due to limited resources. In such circumstances, management by an obstetrician or obstetric general practitioner knowledgeable in GDM management, often with the assistance of an appropriately skilled dietitian, diabetes educator or midwife, is acceptable. Patient education The importance of educating women with GDM (and their partners) about the condition and its management cannot be overemphasised. Compliance with the treatment plan depends on the patient's understanding of: The implications of GDM for her baby and herself; The dietary and exercise recommendations; and The how and when as well as the goals of self monitoring of blood glucose level. Care should be taken to minimise the anxiety of the women. Glycaemic control Dietary therapy: Dietary therapy is the primary therapeutic strategy for the achievement of acceptable glycaemic control in GDM. All women should receive nutritional advice, preferably from an appropriately skilled dietitian. However, it is important to avoid a severe calorie-restricted diet, as this can predispose to ketonuria, and also to infants that are small for their gestational age, which carries an increased risk of diabetes in later life.25 The diet needs to: Conform with the principles of dietary management of diabetes in general; Meet the nutritional requirements of pregnancy; Be individualised for each patient, depending on maternal weight and body mass index; and Be culturally appropriate. Moderate exercise has recently been recognised as an adjunct therapy, with potential benefits when used together with diet, or diet and insulin therapy, in the management of gestational diabetes in women without a medical or obstetric contraindication.26 Monitoring: Glycaemic control needs to be monitored. Self monitoring of blood glucose level is the optimal method and is well tolerated by most women. On commencement of self monitoring, at least one fasting and one 1 or 2 hour postprandial glucose level should be obtained daily. The frequency may be decreased or increased depending on the results of the blood glucose monitoring and the progress of the pregnancy. If self monitoring is not possible, fasting and 1 or 2 hour postprandial laboratory capillary blood or venous plasma glucose levels should be performed regularly (at 1 to 2 weekly intervals). In pregnancies complicated by GDM, the value of self monitoring of blood glucose and appropriate insulin therapy in the prevention of macrosomia and its associated perinatal complications has previously been demonstrated.27,28 The minimum goals for glycaemic control are: a fasting capillary (venous plasma) blood glucose level <5.5 mmol/L a 1 hour postprandial capillary (venous plasma) blood glucose level <8.0 mmol/L a 2 hour postprandial capillary (venous plasma) blood glucose level <7.0 mmol/L. These minimum goals have been set on the basis of informed consensus opinion in Australasia and vary little from those of the American Diabetes Association clinical practice recommendations on gestational diabetes (fasting glucose ≤5.8 mmol/L and 2 hour postprandial plasma glucose ≤6.7 mmol/L).29 The setting of minimal goals for glycaemic control is controversial, however, as some, but not all, studies show benefit from tight glycaemic control in women with GDM.27,28,30-32 The reasons for the variance in results between studies may relate to differences in the underlying rates of GDM complications from one study population to another. The recommended fasting glycaemia goal of <5.5 mmol/L is supported by Langer et al, who have shown that rates of large-for-gestational-age (LGA) infants are increased in diet-treated GDM pregnancies if the fasting glucose level is between 5.3 and 5.8 mmol/L (28.6% LGA) compared with ≤5.3 mmol/L (5.35% LGA).32 Insulin treatment was shown to reduce the rates of LGA infants to 10.3% in GDM pregnancies with fasting glucose levels between 5.3 and 5.8 mmol/L.32 In support of the 1 and 2 hour postprandial glycaemic goals of <8.0 and <7.0 mmol/L, respectively, it has been shown that glycohaemoglobin (HbA1c) levels, birth weight, and rates of macrosomia, neonatal hypoglycaemia and caesarean section (for cephalopelvic disproportion) can all be significantly reduced in insulin-treated GDM subjects if insulin therapy is adjusted according to 1 hour postprandial, rather than preprandial, glucose measurements, aiming for <7.8 mmol/L.27 HbA1c levels may be used as an ancillary test, as assurance that the self monitored blood glucose results are appropriate. Fructosamine levels are reduced during pregnancy because of the dilutional effect of pregnancy on plasma proteins. HbA1c and fructosamine are not reliable substitutes for self monitoring of blood glucose level. Insulin therapy: Insulin therapy should be considered if the blood glucose goals are exceeded on two or more occasions within a 1 to 2 week interval, particularly in association with clinical or investigational suspicion of macrosomia. However, the benefit of instituting insulin therapy after 38 weeks' gestation is unproven. Human insulin should be used. No insulin preparations have a pregnancy category listing, except for the new, rapidly acting insulin analogue lispro, which is Category B2 (Australian medicines in pregnancy category). Two cases of congenital malformations were recently noted in women with insulin-dependent diabetes treated in pregnancy with lispro.33 The number of women treated with lispro in pregnancy is small to date, but no causative relationship between lispro and teratogenicity has been documented. In general, the insulin preparations and dosage schedules should be tailored to the abnormalities present in the glycaemic profile (eg, postprandial and/or fasting hyperglycaemia) and patient acceptability. The doses may be higher than those required in non-pregnant subjects and should be reviewed frequently so that adequate glycaemic control is achieved rapidly. Care should be taken to minimise the risk of hypoglycaemia, especially nocturnal episodes. Oral hypoglycaemic agents have no place in treatment of GDM under normal circumstances. Fetal surveillance The timing of commencement and the frequency of fetal monitoring in pregnancies complicated by GDM depend on the presence of other pregnancy complications such as pre-eclampsia, hypertension, antepartum haemorrhage and intrauterine growth retardation. The regimen chosen should be dictated by the severity of the obstetric complication. Monitoring may be by either Doppler umbilical bloodflow measurement or cardiotocograph (CTG). Although CTG surveillance is commonly undertaken routinely from around 36 weeks' gestation, there is no objective evidence that fetal monitoring in uncomplicated GDM affects fetal outcome.34 Common practice in the United States is to commence CTG monitoring after 40 weeks' gestation, while awaiting spontaneous onset of labour in uncomplicated GDM pregnancies,35 but again there is no evidence-based medicine to support or refute this practice. Ultrasonography should be considered at around 34 weeks' gestation to detect abnormalities of fetal growth and polyhydramnios. It may be indicated earlier in some women, for example for women unsure of their dates, or those with morbid obesity or suspected undiagnosed non-insulin-dependent diabetes. Ultrasonography may need to be repeated if any abnormality is detected. Timing of delivery The possibility that diagnosis of GDM may lead to increased obstetric intervention, including induction of labour and caesarean section,36 is a concern. Delivery before full term is not indicated unless there is evidence of macrosomia, polyhydramnios, poor metabolic control or other obstetric indications (eg, pre-eclampsia or intrauterine growth retardation).37 Continuation of the pregnancy in uncomplicated GDM to 10 days beyond term is acceptable provided that indications from fetal monitoring are reassuring. Delivery During labour, good glycaemic control needs to be maintained while avoiding hypoglycaemia. Lower insulin requirements are common during labour (often no insulin is necessary). Fetal surveillance is needed, as it is for any high risk pregnancy. A paediatrician should be present at the delivery if significant neonatal morbidity is suspected. The maternal blood glucose level should be monitored for 24 hours postpartum and, if indicated, continued for longer. Neonatal management The neonates of mothers with GDM are at risk of all the complications of infants born to mothers with overt diabetes, particularly those infants born macrosomic (birth weight >4000 g).38 The neonates should be observed closely after delivery for respiratory distress. Capillary blood glucose should be monitored at 1 hour of age and before the first four feeds (and for up to 24 hours in high risk neonates). Currently, some amperometric blood glucose meters are acceptable for use in neonates, provided that suitable quality control procedures and operator training are in place. A neonatal blood glucose level <2.0 mmol/L needs to be verified by repeat testing (laboratory verification is preferred but should not delay the initiation of treatment). Levels <2.0 mmol/L should be considered abnormal and treated. If the baby is obviously macrosomic, calcium and magnesium levels should be checked on Day 2. Breastfeeding is actively encouraged. Maternal follow-up It is important that women with GDM be counselled with regard to their increased risk of developing permanent diabetes. They should be made aware of the symptoms of hyperglycaemia. Advice should be given about the importance of healthy eating and exercise patterns. Contraceptive advice should be given in the puerperium, and women should be advised to plan future pregnancies and be reviewed medically by their general practitioner before conception (a pre-conception OGTT should be considered). An OGTT, using WHO criteria for the non-pregnant population, should be performed at 6-8 weeks' postpartum to exclude permanent diabetes. Repeat OGTTs should be performed at least every two years (possibly at the same time as the cervical cancer screening). Impaired glucose tolerance merits careful follow-up, which should include at least twice-yearly checks for frank diabetes in addition to assessment of other risk factors for macrovascular disease. The rates of development of permanent diabetes are much higher in several non-European ethnic groups. For example, the prevalence of type 2 diabetes in Polynesian women having a postpartum OGTT has been reported to be 30%.39 Life-table analysis in a cohort of Latino women shown to have normal glucose tolerance in the postpartum period after pregnancy complicated by GDM revealed a 47% cumulative incidence of type 2 diabetes 5 years after delivery.40 Similarly, 62% of women in Trinidad have been reported to develop type 2 diabetes after 3.6-6.5 years of follow-up.41 Follow-up OGTTs, therefore, should be more frequent than every two years in those groups at highest risk. Directions for future research ADIPS emphasises that, due to a lack of good quality randomised controlled clinical trials in the area of GDM, these guidelines are based on what is a reasonable consensus of informed opinion in Australasia. They are designed as a guide to practical management rather than a strict protocol. It is expected that the guidelines will not be static but will evolve as the results of clinical trials become available. Carefully designed, randomised controlled clinical trials are needed in order to determine: Whether universal screening programs are warranted; The optimal criteria for diagnosis of GDM; The costs v. benefits of the team approach; Optimal management (eg, clarification of the indications for insulin therapy); The role of follow-up programs for affected mothers and babies; and Possible interventions to reduce the rates of development of permanent diabetes in the mother. One such trial is the prospective Australasian Carbohydrate Intolerance Study in Pregnancy (ACHOIS), which aims to clarify what degree of maternal hyperglycaemia results in specific adverse outcome. In the design of these trials consideration needs to be given not only to perinatal outcome, but also to the potential long term benefits of diagnosis and treatment for both the baby and the mother. Acknowledgements The assistance of all members of ADIPS who contributed to the consensus statement is gratefully acknowledged. Valerie Arnol's assistance is also gratefully acknowledged. References Metzger BE, editor. Proceedings of the third international workshop-conference on gestational diabetes mellitus. Diabetes 1991; 40 Suppl 2: 1-201. O'Sullivan JB, Charles D, Mahan CM, Dandrow RV. Gestational diabetes and perinatal mortality rate. Am J Obstet Gynecol 1973; 136: 901-904. Pettitt DJ, Knowler WC, Baird HR, Bennett PH. Gestational diabetes: infant and maternal complications of pregnancy in relation to third trimester glucose tolerance in Pima Indians. Diabetes Care 1980; 3: 458-464. Oats JN, Beischer NA. Gestational diabetes. Aust N Z J Obstet Gynaecol 1986; 26: 2-10. Hod M, Merlob P, Friedman S, et al. Gestational diabetes mellitus: a survey of perinatal complications in the 1980s. Diabetes 1991; 40 (Suppl 2): 74-78. Van Asche FA, Aerts L, Holemans K. The effects of maternal diabetes on the offspring. Baillieres Clin Obstet Gynaecol 1991; 5: 485-492. Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers: relationship to fetal hyperinsulinism. Diabetes Care 1995; 18: 611-617. Pettitt DJ. Diabetes in subsequent generations. In: Dornhurst A, Hadden DR, editors. Diabetes and pregnancy: an international approach. Chichester: J Wiley and Sons, 1996: 367-376. Simmons D, Robertson S. Influence of maternal insulin treatment on the infants of women with gestational diabetes. Diabet Med 1997; 14: 762-765. O'Sullivan JB. The Boston Gestational Diabetes Studies: review and perspectives. In: Sutherland HW, Stowers JM, Pearson DWM, editors. Carbohydrate metabolism in pregnancy and the newborn. London: Springer-Verlag, 1989: 287-294. Greene MF. Screening for gestational diabetes. N Engl J Med 1997; 337: 1625-1626. Jarrett RJ. Should we screen for gestational diabetes? BMJ 1997; 315: 736-737. Soares J de AC, Dornhurst A, Beard RW. The case for screening for gestational diabetes. BMJ 1997; 315: 737-739. Moses RG, Colagiuri S. The extent of undiagnosed gestational diabetes mellitus in New South Wales. Med J Aust 1997; 167: 14-16. Beischer NA, Oats JN, Henry OA, et al. Incidence and severity of gestational diabetes mellitus according to country of birth in women living in Australia. Diabetes 1991; 40: 35-38. Beischer NA, Wein P, Sheedy MT, Steffen B. Identification and treatment of women with hyperglycaemia diagnosed during pregnancy can significantly reduce perinatal mortality rate. Aust N Z J Obstet Gynaecol 1996; 36: 239-247. Moses R, Griffiths R, McPherson S. The incidence of gestational diabetes in the Illawarra area of New South Wales. Aust N Z Obstet Gynaecol 1994; 34: 425-427. Martin FIR, Ratnaike S, Wootton A, et al. The 75 g oral glucose tolerance in pregnancy. Diabetes Res Clin Pract 1995; 27: 147-151. Yue DK, Molyneau LM, Ross GP, et al. Why does ethnicity affect prevalence of gestational diabetes? The underwater volcano theory. Diabet Med 1996; 13: 748-752. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997; 20: 1183-1197. Naylor CD, Sermer M, Chen E, Farine D. Selective screening for gestational diabetes mellitus. N Engl J Med 1997; 337: 1591-1596. Martin FIR. The diagnosis of gestational diabetes. Med J Aust 1991; 155: 112. O'Sullivan JB, Mahan CM. Criteria for the oral glucose tolerance test in pregnancy. Diabetes 1964; 13: 278-285. World Health Organization Study Group, Diabetes Mellitus. World Health Organ Tech Rep Ser 1985; 727: 13-14. McCance DR, Pettitt DJ, Hanson RL, et al. Birth weight in non insulin dependent diabetes. Thrifty genotype, thrifty phenotype or surviving small baby genotype? BMJ 1994; 308: 942-945. Jovenovic-Peterson L, Peterson CM. Is exercise safe or useful for gestational diabetic women? Diabetes 1991; 40 Suppl 2: 179-181. De Veciana M, Major CA, Morgan MA, et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med 1995; 333: 1237-1241. Langer O, Rodriguez DA, Xenakis EMJ, et al. Intensified versus conventional management of gestational diabetes. Am J Obstet Gynecol 1994; 170: 1036-1047. American Diabetes Association: clinical practice recommendations 1997. Diabetes Care 1997; 20 Suppl 1: S1-S70. Hare JW. Gestational diabetes mellitus. Levels of glycemia as management goals. Diabetes 1991; 40 Suppl 2: 193-196. Garner P, Okun N, Keely E, et al. A randomized controlled trial of strict glycemic control and tertiary level obstetric care versus routine obstetric care in the management of gestational diabetes: a pilot study. Am J Obstet Gynecol 1997; 177: 190-195. Langer O, Berkus M, Brustman L, et al. Rationale for insulin management in gestational diabetes mellitus. Diabetes 1991; 40 Suppl 2: 186-190. Diamond T, Kormas N. Possible adverse effect of insulin lispro. N Engl J Med 1997; 337: 1009-1010. Landon MB, Langer O, Gabbe SG, et al. Fetal surveillance in pregnancies complicated by insulin-dependent diabetes mellitus. Am J Obstet Gynecol 1992; 167: 617-621. Carr DB, Gabbe S. Gestational diabetes: detection, management and implications. Clin Diabetes 1998; 16: 4-11. Hunter DJS, Keirse MJNC. Gestational diabetes. In: Chalmers I, Enkin M, Keirse MJ NC, editors. Effective care in pregnancy and childbirth. Vol 1. Oxford: Oxford University Press, 1989: 403-410. Rasmussen MJ, Firth R, Roley M, Stronge JM. The timing of delivery in diabetic pregnancy: a 10-year review. Aust N Z J Obstet Gynaecol 1992; 32: 313-317. Maresh M, Beard RW, Bray CS, et al. Factors predisposing to and outcome of gestational diabetes. Obstet Gynaecol 1989; 74: 542-546. Simmons D, Conroy C, Thompson C. Diabetes in pregnancy in South Auckland. Proceedings of the Australasian Diabetes in Pregnancy Society Annual Scientific Meeting, Melbourne, 1995. Melbourne: ADIPS, 1995: 55. Kjos SL, Peters RK, Xiang A, et al. Predicting future diabetes in Latino women with gestational diabetes. Utility of early postpartum glucose tolerance testing. Diabetes 1995; 44: 586-591. Ali Z, Alexis SD. Occurrence of diabetes mellitus after gestational diabetes mellitus in Trinidad. Diabetes Care 1990; 13: 527-529. Authors' details Department of Diabetes and Endocrinology, Royal Hobart Hospital, Hobart, TAS. Linda Hoffman, MD, FRACP, Visiting Specialist. School of Nutrition and Public Health, Deakin University, and Geelong Hospital, Geelong, VIC. Chris Nolan, PhD, FRACP, Postdoctoral Research Fellow, and Visiting Specialist. Department of Endocrinology, The Canberra Hospital, Canberra, ACT. J Dennis Wilson, MD, FRACP, Director of Endocrinology. Master Misericordiae Mothers' Hospital, South Brisbane, QLD. Jeremy J N Oats, DM, FRACOG, Director, and Clinical Professor of Obstetrics and Gynaecology. Department of Medicine, Middlemore Hospital, University of Auckland, Auckland, New Zealand. David Simmons, MD, FRACP, Senior Lecturer in Medicine. Reprints: Associate Professor L Hoffman, Department of Diabetes and Endocrinology, Royal Hobart Hospital, 48 Liverpool Street, Hobart, TAS 7001. - Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For 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>". <URL: http://www.mja.com.au/>

Linda Hoffman · Chris Nolan · David Simmons

Tuberculosis in children in Australia: strategies for control David Isaacs and Craig M Mellis, on behalf of the Paediatric Special Interest Group of the Australasian Society for Infectious Diseases* and the Australasian Paediatric Respiratory Group** MJA 1998; 168: 121-124 Introduction - Epidemiology - Childhood tuberculosis - Child advocacy - Control of tuberculosis - Acknowledgements - References - Paediatric Special Interest Group of ASID - Australasian Paediatric Respiratory Group - Authors' details - - ©MJA1998 Introduction Globally, tuberculosis (TB) is responsible for more deaths per year than any other infection. The World Health Organization estimated that in 1990 there were 7.5 million new cases of TB; 1.3 million were in children under 15 years of age, of whom 450 000 died.1 TB is relatively rare in Australian children, but, because of the associated high morbidity and mortality and the risk of later reactivation of disease, it should not be neglected. This paper outlines strategies to control paediatric TB. Tuberculosis in childhood is different from that in adults, and requires different expertise. This position paper, a consensus by paediatric infectious disease and respiratory specialists, outlines strategies for managing childhood TB in Australia. A companion paper, in preparation, will address strategies applicable to New Zealand. A further paper will deal with specific details of management of paediatric tuberculosis, including diagnosis and treatment. Epidemiology While the incidence of TB in industrialised countries has fallen to very low levels with improving living conditions, in the United States the steady decline in incidence of TB has halted. From 1985 to 1992 there was a 20% increase in reported cases in both adults and children1-4 (although this situation has now improved5 ). Further, the US has experienced an increase in the prevalence of infection with multidrug-resistant strains of TB.2,4 This increase was the result of an association of HIV infection and TB, increasing poverty, immigration from countries with high TB prevalence, and decreased public health funding.4,5 The re-emergence of TB as a problem in the USA has caused other industrialised countries to re-examine policies for the prevention and management of this disease. Tuberculosis is not presently a major problem in Australia. Its incidence has remained stable since 1986 at 5.5-6.0 cases per 100 000 population per year.6-9 The number of notified cases in children aged 0-14 years has fallen from 70 in 1991, to 45 in 1992, 37 in 1993, and 33 in 1994.7-9 Two childhood deaths from TB were notified in 1992; none have been notified since. While most TB notifications are made from New South Wales and Victoria, the rate of notifications is highest in the Northern Territory. The notification rate is lowest in non-indigenous Australian-born people (1.5-2.0 per 100 000), while Aboriginality is associated with a higher incidence (10-13 per 100 000).8,9 However, being born overseas is associated with an even higher incidence, which has been consistently reported at around 15 per 100 000 for the past three years.7-9 Childhood tuberculosis Starke10 has emphasised the differences between paediatric and adult tuberculosis. Children generally have a much smaller bacterial population and there is less secondary resistance. Cavitary lesions are very rare, but children have a greater propensity for extrapulmonary disease. While children tolerate higher doses of medication relative to body weight, with lower rates of adverse reactions, paediatric formulations (syrups or soluble powders) are not always available. Paediatric tuberculosis is usually acquired from contact with an infected adult, and children with TB are generally at low risk of infecting others. Child advocacy In Australia, children with suspected or proven tuberculosis may be managed by paediatricians, at adult chest clinics, or by specialists in paediatric or adult infectious diseases.9 Given the low incidence of childhood cases, this variety of attending specialists is not surprising and does not necessarily mean that current management of paediatric TB is inappropriate. In large cities there may be enough children with TB or receiving preventive therapy to warrant specialised paediatric TB clinics that combine both paediatric and public health expertise. However, in many parts of Australia, children with TB or TB contact are managed in chest clinics by chest physicians who are expert in tuberculosis, but may lack paediatric knowledge and skills. On the other hand, the regional paediatrician, with experience in examining and managing children, may have little knowledge and experience of childhood tuberculosis. Although paediatric TB is rare, child contacts of adults with TB are much less rare, and preventive therapy of children requires expert knowledge and supervision.3,10 Guidelines on tuberculosis concentrate on adult aspects of TB, and tend to neglect paediatric aspects.11-13 As paediatricians are child advocates and experts in child health, they should be more involved in the care of children with TB,14 not necessarily as sole carers, but at least in consultation. Paediatricians can provide clinical expertise and advice in areas such as compliance with medication, particularly for very young children. Recommendation: Paediatricians should be consulted and involved in the management of TB in children whenever possible. [Consensus view, not addressed by the NHMRC TB Working Party.11] Control of tuberculosis The most critical aspect of control of tuberculosis is the existence of appropriate public health programs. The important strategies in TB control are: BCG vaccination; Screening of children at high risk; Contact tracing; and Appropriate duration of drug therapy. BCG vaccine Bacille Calmette-Guerin (BCG) vaccine was first used in humans in 1921, and few attempts have been made since then to develop improved vaccines against TB. BCG vaccine is moderately effective: a recent meta-analysis15 gave its protective efficacy as 50% against any TB disease, 64% against TB meningitis, and 71% against death from TB. Occasional cases of TB meningitis occur in children in Australia6-9 and might be prevented by BCG vaccination. The NHMRC TB Working Party currently recommends BCG vaccination for three groups of children:11 Aboriginal and Torres Strait Islander neonates in regions of high incidence; Neonates born to patients with leprosy (because of cross-protection by BCG against leprosy); and Children under the age of five years who will be travelling to live in countries of high TB prevalence for long periods. The NHMRC TB Working Party11 states that BCG vaccine should be considered for: Neonates who will be living in a household which includes immigrants or visitors recently arrived from countries of high TB prevalence (and neonates in families who have returned to visit the homes of relatives in countries of high prevalence); and Children and adolescents aged less than 16 years who continue to be exposed to a patient with active TB, and where the child or adolescent cannot be given preventive isoniazid therapy, or the person with active disease has organisms resistant to both rifampicin and isoniazid. We believe these latter two "considerations" should be changed to "recommendations" to prevent occasional, but devastating, cases of tuberculosis in these children. In particular, neonates whose parents are from South-East Asia or the Indian subcontinent should be given BCG at birth. There is currently no information on how many children receive BCG vaccine in Australia each year, either as an absolute number or as a proportion of those eligible. Clearly, such information would be a great advantage in analysing BCG vaccine efficacy, and thus in evaluating the current NHMRC recommendations. The Australian Childhood Immunisation Register, implemented in 1996, monitors compliance with some vaccines, but not with BCG as yet. Studies are needed on the proportion of eligible children who receive BCG vaccine, and on side effects of BCG vaccination. Recommendations: We support the indications for BCG vaccination as recommended by the NHMRC TB Working Party, but feel that BCG should be recommended in all five situations detailed above. [Consensus opinion based on the high rate of TB in children exposed to adults with TB. This recommendation has also been made in the Australian immunisation procedures handbook,16 but not by the NHMRC TB Working Party,11 in 1989.] We strongly urge the Federal Government to put in place mechanisms to audit the number of children vaccinated with BCG vaccine each year. [Consensus opinion.] Mantoux screening In Australia, Mantoux skin testing is usually performed with 10 tuberculin units of purified protein derivative (PPD), although one unit only may be used if there is a high risk of TB.16 In the United States,17 Mantoux skin testing is performed with five tuberculin units of PPD. US authorities' interpretation of a positive Mantoux skin test is shown in the Box; there is currently no recognised Australian interpretation of skin test positivity. At present, the Committee on Infectious Diseases of the American Academy of Pediatrics (the "Red Book" committee)17 recommends annual tuberculin testing of children at high risk, but not of children at low risk. Six months of isoniazid preventive therapy is recommended for children who are Mantoux positive without disease,12 as this is as effective as nine months' duration of therapy18 and has a better risk-benefit analysis.19 While Australian children are not routinely tested with tuberculin, two recent surveys of the Mantoux status of 13-year-old20 and six-year-old21 Sydney schoolchildren showed t hat being born overseas was the major risk factor for being Mantoux-positive. In addition, the later the child left the country of birth, the greater the risk of being Mantoux- positive. Australian-born children with one or both parents born overseas were not at increased risk of being Mantoux- positive compared with Australian-born children of Australian-born parents. As most Mantoux-positive children in Australia were born overseas, it is important to screen children who are migrating to Australia from countries with a high prevalence of TB. Short visits (e.g., holidays) overseas are associated with a low risk of becoming infected with TB. Although short term visitors to Australia occasionally transmit TB, screening them would be extremely difficult, and this is not done routinely. However, screening might be indicated in special circumstances (e.g., a visitor from a high endemic area with chronic respiratory symptoms). Routine annual Mantoux screening is not justified by the available data. Recommendations: Children born overseas who are migrating to Australia from a country with a high prevalence of tuberculosis should be screened by Mantoux testing with or without a chest x-ray on entry into Australia. [Based on evidence,20,21 but not currently recommended by the NHMRC TB Working Party.11] Children born in Australia should not be screened annually by Mantoux testing. [Based on evidence20,21 and consistent with NHMRC TB Working Party recommendations.11] Visitors to Australia from areas of high TB incidence should not be routinely screened, but neonates exposed to such visitors should be vaccinated with BCG. [Consensus opinion, consistent with Australian immunisation procedures handbook.16] Mantoux-positive children with no evidence of TB disease should be given preventive therapy with isoniazid for six months. [Based on evidence18,19 and consistent with NHMRC TB Working Party recommendations.11] Contact tracing Diligent tracing of the adult source of paediatric TB infection through public health networks continues to be an important step in preventing the spread of TB. Appropriate duration of drug therapy The emergence of highly resistant and multiply resistant strains of M. tuberculosis has re-emphasised the importance of good management of TB, and the development of innovative management and control strategies. The emergence of resistant strains is thought to be the result of failure of patients with TB to complete courses of chemotherapy. In New York, this was a consequence of failure to supervise patients' therapy as a result of cuts in health funding in the 1980s.4,5 In Australia, some States supervise all antituberculous therapy, while others use targeted supervision of patients considered to be at risk of being non-compliant. In general, there are insufficient public health staff to ensure supervision of preventive therapy with isoniazid. Continued supervision of therapy (either full or targeted supervision) is important to prevent the emergence of resistant strains in Australia, and requires funding. Recommendation: Specifically funded TB control programs need to be maintained in each State and Territory in Australia. [Consensus opinion.] This document has been discussed by the Writing Panel of the Paediatric Special Interest Group of the Australasian Society for Infectious Diseases (ASID), circulated to all members, and ratified by the ASID Council. It was discussed at the 1996 meeting of the Australasian Paediatric Respiratory Group, and circulated to all members for comment. It was sent to Dr Greg Stewart, Chair of the NHMRC Working Party on Towards elimination of tuberculosis II. Guidelines and protocols for controlling tuberculosis disease in Australia, and to the Public Health Association of Australia. Acknowledgements Helpful comments were received from Dr T Konstantinos, Dr Graeme Oliver, Dr Graham Simpson and Professor Louis Landau. References Raviglione MC, Snider DE, Kochi A. Global epidemiology of tuberculosis. Morbidity and mortality of a worldwide epidemic. JAMA 1995; 273: 220-226. Report from the Centers for Disease Control and Prevention: tuberculosis morbidity, United States, 1992. JAMA 1993; 270: 1525. Starke JR, Jacobs RF, Jereb J. Resurgence of tuberculosis in children. J Pediatr 1992; 120: 839-855. Drucker E, Alcabes P, Bosworth W, Schell B. Childhood tuberculosis in the Bronx, New York. Lancet 1994; 343: 1482-1485. Frieden TR, Fujiwara PI, Washro RM, Hamburg MA. Tuberculosis in New York City -- turning the tide. N Engl J Med 1995; 333: 229-233. Cheah D. Tuberculosis notification rates, Australia, 1991. Commun Dis Intell 1992; 16: 398-400. Hargreaves J. Tuberculosis notifications in Australia, 1992. Commun Dis Intell 1994; 18: 330-337. Hargreaves J. Tuberculosis notifications in Australia, 1993. Commun Dis Intell 1995; 19: 332-341. Oliver G. Tuberculosis notifications in Australia, 1994. Commun Dis Intell 1996; 20: 108-115. Starke JR. Multidrug therapy for tuberculosis in children. Pediatr Infect Dis J 1990; 9: 785-793. National Health and Medical Research Council. Tuberculosis in Australia and New Zealand into the 1990s. Canberra: AGPS, 1989. Grossman M, Hopewell PC, Jacobs RF, et al. Consensus: management of tuberculin-positive children without evidence of disease. Pediatr Infect Dis J 1988; 7: 243-246. NSW Health Department. Controlling tuberculosis in New South Wales. Sydney: NSW Health, 1993. Forfar JO. Child health in a changing society. Oxford: Oxford University Press, 1988. Colditz GA, Brewer TF, Berkey JCS, et al. Efficacy of BCG vaccine in the prevention of tuberculosis. JAMA 1994; 271: 698-702. National Health and Medical Research Council. The Australian immunisation procedures handbook. 6th ed. Canberra: AGPS, 1997. American Academy of Pediatrics. Report of the Committee on Infectious Diseases. 23rd ed. Illinois: The Academy, 1994. Comstock GW, Baum G, Snider DE Jr. Isoniazid prophylaxis among Alaskan Eskimos. Am Rev Respir Dis 1979; 119: 827-830. International Union Against Tuberculosis, Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis. Five years of follow-up in the IUAT trial. Bull World Health Organ 1982; 60: 555-564. Alperstein G, Fett MJ, Reznik R, et al. The prevalence of tuberculosis infections among Year 8 school children in inner Sydney in 1992. Med J Aust 1994; 160: 197-201. Alperstein G, Morgan K, Fett MJ, et al. Prevalence of tuberculosis infection among primary school entry children in Sydney. Aust J Pub Health 1996; 20: 123-128. *Paediatric Special Interest Group of ASID R Benn, MA Burgess, D Burgner, D Caplan, J Carapetis, P Collignon, R Doherty, G Eagles, J Faoagali, M Ferson, K Forsyth, S Garland, GL Gilbert, D Gordon, K Grimwood, J Hanna, D Hansman, G Hogg, D Holdaway, M Holloway, D Isaacs, H Jeffery, C Jones, A Kakakios, A Kesson, D Lennon, D McCrossin, P McIntyre, A McGregor, D McIntosh, M Nissen, D Roberton, R Robins-Brown, J Robson, J Royle, L Voss, S Wesselingh, J Whitson, B Wild, A Yung. The writing panel of the Paediatric Special Interest Group of ASID comprised GL Gilbert, MA Burgess, M Ferson, S Garland, K Grimwood, G Hogg, D Isaacs, and P McIntyre. **Australasian Paediatric Respiratory Group H Allen, I Asher, P Van Asperen, G Bowes, B Clements, D Cooper, P Cooper, K Dawson, P Field, P Francis, N Freezer, J Gillies, M Haifer, M Harris, R Henry, A Isles, A Kemp, D Kennedy, L Landau, J Martin, CM Mellis, S Sawyer, B Masters, J Morton, T Olinsky, P Pattemore, P Phelan, C Robertson, P Robinson, P Sly, G Smith, P Le Souef, R Staugas, S Stick. Authors' details Australasian Society for Infectious Diseases, Sydney, NSW. David Isaacs, FRACP, Member of the Paediatric Special Interest Group; Craig M Mellis, FRACP, Member of the Australasian Paediatric Respiratory Group. Reprints will not be available from the authors. Correspondence: Associate Professor D Isaacs, Department of Immunology and Infectious Diseases, Royal Alexandra Hospital for Children, Westmead, NSW 2145. E-mail: davidi AT rich.edu.au - Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For 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>". <URL: http://www.mja.com.au/>

Consensus Statement Glycohaemoglobin: a crucial measurement in modern diabetes management Progress towards standardisation and improved precision of measurement* Peter G Colman, G Ian Goodall, Peter Garcia-Webb, Paul F Williams and Marjorie E Dunlop MJA 1997; 167: 96-98 Introduction - What is glycohaemoglobin and why should we measure it? - Types of assays available - Importance of reproducible measurement - How reliable are assays in Australia? - Progress towards standardisation - References - Authors' details - - More articles on Endocrinology Abstract Synopsis There are currently four principal glycohaemoglobin assay techniques (ion-exchange chromatography, electrophoresis, affinity chromatography and immunoassay) and about 20 different methods that measure different glycated products and report different units. Standardisation will lead to all assays reporting results in a standard unit, the HbA1c percentage of total serum haemoglobin, and should be in place within the next one to three years. In the interim, clinicians using glycohaemoglobin assays should be aware that the ranges indicating good and poor glycaemic control can vary markedly between different assays. The reproducibility of some assays may be insufficient to provide definitive evidence of changes in glycaemic control. Some assays may be so imprecise that they are unable to separate patients with good and poor control. Interim recommendations The terminology to be used for the assay is glycohaemoglobin (GHb) assay (recommendation from the combined meetings of the International Federation of Clinical Chemistry [IFCC] Working Group on HbA1c standardisation and the American Association of Clinical Chemistry [AACC] Subcommittee on Glycohemoglobin). The unit of measurement for GHb assays should be reported as %HbA1c (Diabetes Control and Complications Trial equivalent). Other units, such as % total GHb or %HbA1, should not be used. Assays producing these units should be converted to %HbA1c reporting units. Assays with high precision are highly desirable. The IFCC/AACC are currently recommending between-run coefficients of variation of less than 5% for manufacturers of kits and instruments. However, between-run coefficients of variation of less than 3% are far more clinically useful and therefore desirable. Introduction The landmark Diabetes Control and Complications Trial (DCCT)1 has focused increased attention on the importance of glycaemic control in preventing or retarding the progression of complications in patients with diabetes.2 Regular measurement of glycohaemoglobin is now recognised as an essential adjunct to self-measurement of blood glucose in achieving the best possible glycaemic control. However, clinicians using glycohaemoglobin assays should be aware of several potential problems which can confound the interpretation of the glycohaemoglobin result. What is glycohaemoglobin and why should we measure it? Glycohaemoglobin (GHb) is formed by a non-enzymatic interaction between glucose and the amino groups of the valine and lysine residues in haemoglobin. Formation of glycohaemoglobin is irreversible and the level in the red blood cell depends on the blood glucose concentration. Thus, measuring glycohaemoglobin provides a measurement of glycaemic control over time, and its use has been proven to evoke changes in diabetes treatment, resulting in improved metabolic control.3 First introduced in the 1970s, it is now accepted as a unique and important index of metabolic control and was a major outcome measure in the DCCT.1In the DCCT, 1441 patients with insulin-dependent diabetes were randomly allocated to intensive treatment and monitoring (usually with four insulin injections a day or pump treatment) with the aim of achieving normoglycaemia or to conventional treatment (usually with one or two injections a day). The effectiveness of intensive therapy was reflected in clear differences in mean blood glucose and glycohaemoglobin levels between the two groups. The intensive treatment group achieved a mean daily blood glucose level of 8.6 mmol/L and a median HbA1c value of 7.2% compared with the conventional treatment group, which achieved a mean blood glucose level of 12.8 mmol/L and a median HbA1c of 8.9%. These differences in glycaemic control were maintained over a mean period of 6.5 years and were associated with a 35%-76% reduction in retinopathy, nephropathy and neuropathy. Using the knowledge gained in the DCCT, doctors caring for patients with diabetes can now establish targets for glycaemic control that are based on observed outcomes, and which, if met, should minimise the development of complications. Inevitably, because glycohaemoglobin measurements reflect an integrated view of glycaemic control over time, the patients and their carers will place increasing reliance on the glycohaemoglobin result. So it is timely to evaluate the types of assays available, the moves toward standardisation of the reporting units and the precision and reproducibility of current assays. In the DCCT all glycohaemoglobin measurements were performed using the same closely standardised method. Unfortunately, in Australia there are currently four principal glycohaemoglobin assay techniques and about 20 different specific methods, most of which are not standardised between laboratories. Types of assays available The four principal techniques used to measure glycohaemoglobin are ion-exchange chromatography, electrophoresis, affinity chromatography and immunoassay. The techniques measure slightly different glycated products and use at least three different units for reporting the results (%HbA1c, %HbA1 and % total GHb). They can produce different values for the same patient specimen. This was demonstrated in a recent study in which four whole blood samples with HbA1c levels of 5.1% (representing non-diabetes), 6.7% (representing excellent glycaemic control), 8.5% (representing moderate glycaemic control) and 11.4% (representing poor glycaemic control) were distributed to 29 laboratories in Victoria for glycohaemoglobin determinations.4 The range of values obtained for the non-diabetic (4.1%-6.8%), good control (5.1%-9.3%), moderate control (6.7%- 11.9%) and poor control (10.1%-17.3%) specimens demonstrated extensive overlap between measurements of samples from patients with markedly different degrees of glycaemic control (Box 1). At present it is impossible to compare the results from two different laboratories; this can be confusing not only for patients but also for their carers. Laboratory- specific reference ranges are a means by which results from different laboratories can be compared, but the data used to derive such ranges are arbitrary and the categories into which different glycohaemoglobin levels are divided may be misleading. Importance of reproducible measurement A major use of the glycohaemoglobin assay is to assess changes in metabolic control that follow an alteration in treatment. The ability of any assay to reliably detect a change depends on its reproducibility (the ability of the assay and laboratory to get the same answer for the same sample each time). Reproducibility is normally expressed as the coefficient of variation (CV) of an assay. The CV is obtained by measuring the same sample at least 20 times in different assay runs and calculating the mean and standard deviation (SD) of the measurements; the CV is calculated by dividing the SD by the mean and expressing the result as a percentage. An assay with a high CV suffers from poor reproducibility and cannot demonstrate whether glycohaemoglobin levels have changed in different samples. Laboratories normally accept an assay for reporting purposes if the result for quality control samples falls within three SDs of the mean (3SD range). The imprecision of measurement of patient samples will be similar to that of the quality control samples. For example, if the result of an HbA1c assay with good precision (3% CV) was 7%, the 3SD range would be 6.37%-7.63%; for a result of 9%, the 3SD range would be 8.19%-9.81%. These two results can clearly be separated. In contrast, the same results of an assay with poor precision (6% CV) would have 3SD ranges of 5.74%-8.26% (for the 7% level) and 7.38%-10.62% (for the 9% level), and could not be differentiated. How reliable are assays in Australia? The Royal College of Pathologists of Australasia/Australasian Association of Clinical Biochemists Chemical Pathology Quality Assurance Programme provides external quality control samples for Australian laboratories that report glycohaemoglobin levels.5 The program runs on a six-monthly cycle, in which participating laboratories analyse two random samples per month, drawn from lyophilised whole blood samples representing six levels of glycohaemoglobin. The use of lyophilised samples can lead to minor variations in assay values for some methods. However, a recent study has excluded this as a complicating factor.6When measuring control samples with the value of 7.2% HbA1c (the mean outcome of intensive treatment in the DCCT), Australian laboratories reported HbA1c assay results between 6% and 9% HbA1c, while the range of values reported for all units (percentage of HbA1c, HbA1 and total GHb) was between 6% and 12.6%. When measuring control samples with the value of 8.9% HbA1c (the mean outcome level for conventional treatment in the DCCT trial), laboratories reported HbA1c values between 7.4% and 11%, while the range of values for all glycohaemoglobin units was 7.4% to 16.4%. The overlap between values obtained for these samples epitomises the problems currently facing clinicians in interpreting glycohaemoglobin levels and changes in levels reported by different laboratories. The interlaboratory CV obtained varied between 1.6% and 8.9% for the most common assays. To critically evaluate changes in HbA1c, the precision of individual laboratory assays for glycohaemoglobin must be known. For example, the difference in mean HbA1c value between the intensive and the conventional treatment groups in the DCCT was only 1.7%, and any assay used should at least be able to detect a difference of this order. With most laboratories using the 3SD range to accept or reject assay runs, glycohaemoglobin assays with CVs close to 3% are necessary to differentiate the two DCCT group means (Box 2). At 3% CV, the 3SD range of values for a patient with a true HbA1c level of 8.05 %HbA1c would be 7.33 to 8.77 %HbA1c. This range is less than ideal, but, realistically, only high pressure liquid chromatography assays currently achieve such precision. We recommend that the CV of the assay currently being used by the reporting laboratory be made available to carers who use glycohaemoglobin measurements. This will allow them to determine if the assay has the ability to differentiate between reported levels. Reference laboratories in the International Federation of Clinical Chemistry (IFCC)/American Association of Clinical Chemistry (AACC) International Standardization Programme must be able to achieve a CV below 3% at HbA1c levels of 6% and 9%.7 Manufacturers' assays should be able to achieve a CV below 5%. Currently, some GHb assays are unable to achieve these limits. Progress towards standardisation Standardisation is crucial to allow comparison of results obtained in different laboratories. A working party of the IFCC and AACC is coordinating an international effort by which all methods will be standardised to a designated method. This will be performed at the manufacturer level. Glycohaemoglobin analyser and kit manufacturers will have their assays standardised by reference laboratories established and monitored monthly by the IFCC/AACC working party. Thus, ultimately all laboratory methods will report their results in %HbA1c units which have been standardised against the DCCT method.8 Patients and carers will then be able to directly compare their level of glycaemic control against the enormous amount of data obtained by the DCCT trial on the onset and incidence of diabetes-related complications. References Larsen ML, Horder M, Mogensen EF. Effect of long-term monitoring of glycosylated hemoglobin levels in insulin-dependent diabetes mellitus. N Engl J Med 1990; 323: 1021-1025. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin dependent diabetes mellitus. N Engl J Med 1993; 329: 977-986. Yue DK, Colagiuri S, McElduff A, Silink M. Diabetes Control and Complications Trial. Position Statement of the Australian Diabetes Society. Med J Aust 1993; 159: 803-804. Gilbert RE, Goodall I, Young V, Jerums G. Interlaboratory variation of GHb assays in Victoria, Australia. Diabetes Care 1996; 19: 730-734. Goodall I, Gill J, Penberthy L, Gilbert R. Interlaboratory variability of glycohaemoglobin. The Australian experience. In: Proceedings of the International Congress of Clinical Chemistry, 8-12 July, 1996 (editors: Martin SM, Halloran SP). Association of Clinical Biochemists, London, UK. July C 493 (ISSN 0959-9029), London, UK. Weykamp CW, Penders TJ, Muskiet FAJ, van der Slik W. Evaluation of reference material for glycated haemoglobin. Eur J Clin Chem Clin Biochem 1996; 34: 67-72. National Glycohemoglobin Standardization Program (NGSP) (Web site) http://www. missouri.edu/,diabetes/ngsp.html Hoelzel W, Miedema K. Development of a reference system for the international standardisation of HbA1c/glycohemoglobin determinations. J Int Fed Clin Chem 1996; 9: 62-67. * Consensus statement from the Australian Diabetes Society, the Royal College of Pathologists of Australasia and the Australasian Association of Clinical Biochemists Authors' details Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Melbourne, VIC. Peter G Colman, FRACP, MD, Director. Special Chemistry Unit, Austin and Repatriation Medical Centre, Melbourne, VIC. G Ian Goodall, BSc, FAACB, Unit Manager. St John of God Pathology, Perth, WA. Peter Garcia-Webb, MD, FRCPA, Clinical Pathologist. Royal Prince Alfred Hospital, Sydney, NSW. Paul F Williams, MSc, PhD, Principal Hospital Scientist. University of Melbourne Department of Medicine, Melbourne, VIC. Marjorie E Dunlop, MSc, PhD, Principal Research Fellow. Reprints: Dr P G Colman, Department of Diabetes and Endocrinology, Royal Melbourne Hospital, PO Box 3050, Parkville, VIC 3050. E-mail: petercATnursing.medrmh.unimelb.edu.au 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>". <URL: http://www.mja.com.au/> 1: Results of glycohaemoglobin assays of four samples in 29 Victorian laboratories4 The four samples were from patients with differing degrees of diabetes control. The closed circles represent individual laboratory results for each sample and the open circles represent the notional target value. The notional target value was set by the Biorad Diamat (Biorad Laboratories, Hercules, California) in a laboratory where the assay was referenced against the DCCT method.2 Six methods of measuring glycohaemoglobin were used by the laboratories: High pressure liquid chromatography (cation exchange, measuring HbA1c)Immunoassay (measuring HbA1c)Ion exchange chromatography (manual assay, measuring HbA1c or HbA1)Affinity chromatography (measuring total GHb but expressed as either total GHb or %HbA1c)Electrophoresis (measuring HbA1c or HbA1)Low pressure liquid chromatography (measuring HbA1c and including HbF). Back to text Back to text

Peter G Colman · Peter Garcia-Webb · Paul F Williams · Marjorie E Dunlop