Volume 175 Issue 5

Medicine and the Community For editoral comment, see Mason and Diamond; see also Nozza and Rodda Abstract - Methods - Subjects - Assay - Risk assessment - Results - Discussion - Acknowledgements - Reference - Authors' details - - - More articles on Obstetrics & gynaecology and women's health Abstract Objectives: To determine the vitamin D status of veiled or dark-skinned pregnant women, because of their known increased risk of vitamin D deficiency. Design: An audit of vitamin D status. Setting: An antenatal clinic in a major metropolitan teaching hospital, Melbourne, Victoria. Participants: Pregnant women attending the clinic who agreed to be screened. Main outcome measures: Serum 25-hydroxyvitamin D3 (25OHD3) level at first visit to the antenatal clinic. Results: Of 94 women, 82 were screened. Sixty-six women (80%) had 25OHD3 values below the test reference range (22.5-93.8 nmol/L). Conclusions: Our findings are a cause for concern, because vitamin D deficient women are at risk of bone disease and their children at risk of neonatal hypocalcaemia and rickets. Most of our vitamin D comes from the action of ultraviolet light on skin.1 People with a darker skin produce less vitamin D for a given sunlight exposure,1,2 and veiled women, regardless of the climate, are at a high risk of vitamin D deficiency because of their reduced skin exposure to sunlight.3-6 In pregnant women there is the added risk of vitamin D deficiency in the baby. We screened veiled or dark-skinned pregnant women attending an antenatal clinic at a major metropolitan teaching hospital in Melbourne, Victoria, to determine their vitamin D status. Methods Subjects Veiled and/or dark-skinned women attending the antenatal clinic at the Royal Women's Hospital, Melbourne, were advised that they were at increased risk of vitamin D deficiency, putting them at risk of osteomalacia and their children at risk of vitamin D deficiency related problems. Over a 10-month period (July 1999 - April 2000), all such women were asked to provide a blood sample so that their serum level of 25-hydroxyvitamin D3 (25OHD3) could be measured. Those who consented were given a pathology request form for a blood sample to be taken. Assay Serum samples were stored at - 20ºC, and the 25OHD3 assays were performed in batches in the complex chemistry laboratory at the Royal Children's Hospital, Melbourne, using the Incstar radioimmunoassay kit (Dade Behring, Melbourne). The reference range for this test was 22.5-93.8 nmol/L. The coefficient of variation between successive assays at a mean concentration of 43.9 nmol/L was 11.7%. The assay fulfilled the acceptability criteria of the Royal College of Pathologists of Australasia endocrinology quality assurance program. Risk assessment We recorded the date the blood sample was taken (summer was defined as November to April, and winter as May to October); the patient's facial skin colour (fair, intermediate or very dark skinned); and the degree and consistency of skin covering (women who covered their arms and wore a veil or scarf over their hair and neck at all times when outdoors were coded as "consistently covered"; those who uncovered in a private, outdoor environment as "inconsistently covered"; and those who did not generally cover their arms, hair and neck when outdoors as "uncovered"). Results Of 94 veiled or dark-skinned women attending the clinic during the study period, 82 had a blood sample taken. Two did not agree to be tested, and the remaining women did not go to have a blood sample taken. Serum levels of 25OHD3 are shown in Box 1. The median value was 14 nmol/L (range, 3-77 nmol/L). In 66 women (80%) the vitamin D level was below the reference level (< 22.5 nmol/L). Of the women with values below 22.5 nmol/L, 66% (21/32) had blood samples collected in summer and 90% (45/50) in winter (95% CI for difference, 6%-43%; P < 0.01 by χ2 test). Information on skin colour and covering was complete for 70 of the 82 women. The proportion of women with serum 25OHD3 values below 22.5 nmol/L, according to skin colour and covering, is shown in Box 2. Although numbers in some subgroups were extremely small, it did not appear that this additional information was helpful for clinical management. Among the 12 women with missing information, 11 (92%) had vitamin D levels under 22.5 nmol/L, and nine were tested in winter. Discussion Of the dark-skinned and/or veiled pregnant women we tested, 80% were at high risk of vitamin D deficiency, with serum 25OHD3 values below the reference range. The number of veiled and/or dark-skinned pregnant women attending the Royal Women's Hospital each year is not recorded, but, if they were evenly distributed among the five weekly clinics (as appears likely), we estimate that around 560 such women would attend each year. Inadequate sunlight exposure can occur even in Australia, especially among women with a modest dress code or those who limit sunlight exposure for other reasons (eg, valid concerns about the risk of skin cancer). However, vitamin D deficiency can be prevented or treated with dietary supplements. Dark-skinned or veiled women should be screened for vitamin D deficiency and those who are deficient should be given vitamin D supplements, whether or not they are pregnant, because of their high risk of bone disease. Their children are also at risk of vitamin D deficiency and their infants, if breast fed, should be given suitable infant vitamin D supplements (Penta-vite, Roche). We did not measure maternal parathyroid hormone (PTH) levels during the period of this audit, but now do so routinely. PTH is an important marker of bone health in the mother, and there is some evidence that fetal growth is inversely related to maternal PTH level and positively related to maternal calcium level at delivery.7 Research is needed to determine the optimal vitamin D level in pregnant women, in terms of outcome for themselves and their offspring, and to determine whether other groups of women are also vitamin D deficient. Data from Queensland (Associate Professor John McGrath, Director, Department of Psychiatry, University of Queensland, Brisbane, personal communication8) and from the Geelong Osteoporosis Study (Dr Julie Pasco, Study Coordinator, personal communication) suggest that vitamin D deficiency in women of reproductive age is not limited to specific ethnic or cultural groups. Acknowledgements We thank Peter Vervaart and Rhonda Greaves for undertaking the laboratory assays and staff in the Monday clinic at the Royal Women's Hospital for their help. Ruth Morley is supported by the Victorian Health Promotion Foundation (VicHealth). References Norman AW. Sunlight, season, skin pigmentation, vitamin D, and 25-hydroxyvitamin D: integral components of the vitamin D endocrine system. Am J Clin Nutr 1998; 67: 1108-1110. Feleke Y, Abdulkadir J, Mshana R, et al. Low levels of serum calcidiol in an African population compared with a North European population. Eur J Endocrinol 1999; 141: 358-360. el-Sonbaty MR, Abdul-Ghaffar NU. Vitamin D deficiency in veiled Kuwaiti women. Eur J Clin Nutr 1996; 50: 315-318. Ghannam NN, Hammami MM, Bakheet SM, Khan BA. Bone mineral density of the spine and femur in healthy Saudi females: relation to vitamin D status, pregnancy, and lactation. Calcif Tissue Int 1999; 65: 23-28. Taha SA, Dost SM, Sedrani SH. 25-Hydroxyvitamin D and total calcium: extraordinarily low plasma concentrations in Saudi mothers and their neonates. Pediatr Res 1984; 18: 739-741. Gannage-Yared MH, Chemali R, Yaacoub N, Halaby G. Hypovitaminosis D in a sunny country: relation to lifestyle and bone markers. J Bone Miner Res 2000; 15: 1856-1862. Brunvand L, Quigstad E, Urdal P, Haug E. Vitamin D deficiency and fetal growth. Early Hum Dev 1996; 45: 27-33. McGrath JJ, Kimlin MG, Saha S, et al. Vitamin D insufficiency in south-east Queensland [letter]. Med J Aust. 2001; 174: 150-151. (Received 14 Aug 2000, accepted 2 May 2001) Authors' details Royal Women's Hospital, Melbourne, VIC. Sonia R Grover, MD, FRACOG, Obstetrician. Clinical Epidemiology and Biostatistics Unit, Murdoch Children's Research Institute, and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Melbourne, VIC. Ruth Morley, MB BChir, FRCPCH, Senior Research Fellow. Reprints will not be available from the authors. Correspondence: Dr Ruth Morley, Clinical Epidemiology and Biostatistics Unit, Murdoch Children's Research Institute, and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Flemington Road, Parkville, VIC 3052. morleyrATcryptic.rch.unimelb.edu.au Make a comment 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/> Back to text 2: Proportion of women with serum vitamin D (25-hydroxyvitamin D3) levels under 22.5nmol/L, according to skin covering and skin colour Skin colour Skin covering* Very dark Intermediate Light Total Consistently covered 6/6 (100%) 1/2 (50%) 23/25 (92%) 30/33 (91%) Inconsistently covered 3/5 (60%) 1/3 (33%) 18/24 (75%) 22/32 (69%) Uncovered 2/2 (100%) 2/3 (67%) 0 (0) 4/5 (80%) Total 11/13 (85%) 4/8 (50%) 41/49 (84%) 56/70 (80%) *Consistently covered - women always covered up, including arms, hair and neck, when outdoors; inconsistently covered - women did not usually cover fully in their own garden; and uncovered - women did not generally cover their arms, hair and neck when outdoors. Back to text

Sonia R Grover · Ruth Morley

Medicine and the Community Vitamin D deficiency in mothers of infants with rickets Josephine M Nozza and Christine P Rodda MJA 2001; 175: 253-255 For editorial comment, see Mason and Diamond; see also Grover and Morley Abstract - Methods - Clinical audit - Assay - Results - Children - Mothers - Countries of origin - Discussion - References - Authors' details - - More articles on Paediatrics Abstract Objective: To identify infants treated for vitamin D deficiency rickets, and to determine the incidence of vitamin D deficiency in their mothers and their mothers' country of origin. Design: A retrospective audit of the medical records of children diagnosed with vitamin D deficiency rickets. Inpatients were identified by discharge diagnoses of vitamin D deficiency or hypocalcaemia and outpatients by pharmacy dispensing of cholecalciferol. Setting: The Women's and Children's Health Care Network and the Southern Health Care Network (Melbourne, VIC) from June 1994 to February 1999. Patients: 55 children with vitamin D deficiency rickets. Results: Fifty-four of the 55 children were born to mothers with ethnocultural risk factors for vitamin D deficiency. Vitamin D status had been assessed in 31 of the 55 mothers (56%): 25 (81%) had 25-hydroxyvitamin D3 concentrations ≥ 25 nmol/L, consistent with osteomalacia. Conclusion: Vitamin D deficiency continues to occur in children of migrant families. When infants are diagnosed with vitamin D deficiency, vitamin D levels in their mothers and siblings should also be assessed. Vitamin D is the essential precursor of 1,25-dihydroxyvitamin D3, the steroid hormone required for calcium absorption, bone development and growth in children. Ninety per cent of the body's vitamin D is produced in the skin from the action of sunlight (ultraviolet B light), with the remaining 10% coming from dietary sources.1 Ultraviolet light acts on exposed skin only and does not penetrate clothing or glass. Moreover, there is an inverse relationship between the amount of skin pigmentation and vitamin D production. Serum levels of 25-hydroxyvitamin D3 (25OHD3) are a measure of the body's vitamin D stores and used for diagnosing vitamin D deficiency. A serum 25OHD3 level below 40 nmol/L is indicative of vitamin D deficiency, and a level below 25 nmol/L corresponds to osteomalacia or rickets.2 The recommended daily intake (RDI), if there is inadequate sun exposure, is 400 IU in children and 200 IU in adults. Pregnancy increases the RDI for vitamin D to 500-700 IU.3 In newborn infants, vitamin D stores reflect maternal stores, and human breast milk and unfortified cow's milk are poor sources of vitamin D. Vitamin D deficiency is being increasingly recognised in Melbourne.4,5 Reports have focused on infants, not their mothers, and emphasised postnatal factors (unsupplemented breast feeding, reduced sun exposure, dark skin pigmentation and dietary factors) as the cause of vitamin D deficiency. Thus, although vitamin D metabolism is considered to be well understood,6 the importance of adequate maternal sun exposure and its relationship to perinatal vitamin D deficiency appears to be poorly appreciated in clinical practice. We performed a retrospective audit of the medical records of infants diagnosed with rickets to determine the vitamin D status of their mothers and their mothers' country of origin. Methods Clinical audit We examined medical records from the Women's and Children's Health Care Network and the Southern Health Care Network (Melbourne, VIC) for the period June 1994 - February 1999. Inpatients with nutritional vitamin D deficiency were identified by a discharge diagnosis of either hypocalcaemia or vitamin D deficiency rickets. Outpatients with vitamin D deficiency were identified from records of dispensing of cholecalciferol during the study period by the Royal Children's Hospital (RCH) pharmacy. The RCH pharmacy was the sole supplier of cholecalciferol in liquid form in Victoria, so most outpatients prescribed cholecalciferol would have received it from this source. Only patients treated privately with other forms of vitamin D would not be identified this way. Children born at less than 35 weeks' gestation or who had chronic liver or renal disease, or any other underlying systemic disorder, were excluded. Assay From June 1994 to September 1996, the 25OHD3 assay was performed by an inhouse column extraction method, followed by Incstar radioimmunoassay (Incstar Corporation, Stillwater, MN, USA) (reference range, 28-165 nmol/L), and all samples were processed at the Royal Melbourne Hospital. After September 1996, samples were processed at three laboratories in Melbourne and the universal method was changed to the Incstar radioimmunoassay (reference range, 25-108 nmol/L). Results Children Fifty-five children were treated for vitamin D deficiency rickets during the study period. Thirty-six were male and 19 female, with ages ranging from 11 days to 12 years, seven months (mean age, 16 months). Twenty-four of the 55 children (44%) were aged less than 12 months and, of these, 23 were exclusively breast fed at the time of diagnosis. Twenty-three of the 55 children presented in spring (September to November). To confirm the diagnosis, biochemical analyses (serum levels of calcium, phosphate, alkaline phosphatase [ALP], parathyroid hormone [PTH] and 25OHD3 [Box 1]) and radiography of the long bones (showing widened "cupped" and frayed metaphyses and generalised osteopenia) had been performed. Box 1 shows that hypocalcaemia was more likely in children less than 9 months of age, but ALP and/or PTH levels were elevated across all age groups. The children's symptoms at presentation are given in Box 2. Mothers In only 31 (56%) of the 55 children had the 25OHD3 levels of their mothers been measured (Box 3). None of the mothers had volunteered symptoms of vitamin D deficiency at presentation of their children. Three of the children had older siblings diagnosed with rickets, but maternal vitamin D status had not been assessed when the siblings were diagnosed. Twenty-five of the 31 mothers (81%) had 25OHD3 levels of 25 nmol/L or less, consistent with osteomalacia, and 28 (90%) had 25OHD3 levels of 40 nmol/L or less. In seven mothers, further biochemical evaluation had been performed, including calcium, phosphate, ALP and PTH levels. Three women had raised PTH levels indicative of osteomalacia and, after further questioning, two of these mothers described symptoms of osteomalacia. One was a 26-year-old unveiled Ethiopian woman, who complained of back pain, tiredness and occasional hand weakness. The other was a 24-year-old fully veiled Ethiopian woman, who described a seven-month history of carpopedal spasm and musculoskeletal pain. At the time of diagnosis of her 16-month-old child, she was pregnant with her second child. Treatment of this woman not only relieved her symptoms, but prevented the appearance of vitamin D deficiency in her second child. Countries of origin The countries of origin of the 55 mothers were Africa (25; 45%), India/Pakistan (13; 24%), the Middle East (13; 24%) and Italy (3; 5%). The remaining mother was of European descent, but suffered from agoraphobia and depression. Discussion Our findings show that, of the mothers of infants with rickets whose vitamin D levels were measured, most were also vitamin D deficient, but had not complained of symptoms at presentation. Presumably, these women would not otherwise have come to medical attention. Women at particular risk of vitamin D deficiency and osteomalacia are those with dark pigmented skin, reduced sun exposure for ethnocultural reasons (including veiling) and inadequate dietary intake of both calcium and vitamin D.7-9 In children, additional risk factors include maternal vitamin D deficiency and unsupplemented breast feeding, as identified in our study and those of others.9,10 It has been shown by Hoogenboezem et al11 that total vitamin D metabolites in maternal and fetal plasma are closely correlated, indicating that vitamin D stores at birth are dependent on maternal stores. As newborn infants are generally not exposed to direct sunlight and breast milk is a poor source of vitamin D, vitamin D stores, even if normal at birth, may become depleted at eight weeks in infants exclusively breast fed.11,12 We suggest supplementing breast fed infants with 400 IU/day of vitamin D (recommended daily requirement) as the safest option for preventing vitamin D deficiency in infants of at-risk women (in Australia, infant vitamins Penta-vite [Roche] provide 0.45 mL [405 IU] per day). We recommend that when infants with vitamin D deficiency are diagnosed, vitamin D levels in their mothers and siblings should also be assessed, irrespective of whether they are symptomatic. We also recommend that 25OHD3 levels are measured in all pregnant women with dark skin pigmentation and/or limited sun exposure because of veiling. During pregnancy and lactation, these women require 500-700 IU per day of vitamin D. Their infants should also be assessed for vitamin D deficiency. Vitamin D prophylaxis in infants (400 IU per day) should be commenced at birth and continued for the period of breast feeding. References Clemens TL, Adams JS, Henderson SL, et al. Increased skin pigmentation reduces the capacity of skin to synthesize vitamin D3. Lancet 1982; 1: 74-76. Salle BL, Glorieux FH, Lapillone A. Vitamin D status in breastfed term babies. Acta Paediatr 1998; 87: 726-727. Briggs D, Wahlqvist M. Food facts. Chapter 13. Melbourne: Penguin Books, 1984: 119. Pillow JJ, Forrest PJ, Rodda CP. Vitamin D deficiency in infants and children born to migrant parents. J Paediatr Child Health 1995; 31: 180-184. Mayne V, McCredie D. Rickets in Melbourne. Med J Aust 1972; 2: 873-875. DeLuca HF. The vitamin D story: a collaborative effort of basic science and clinical medicine. FASEB J 1988; 2: 224-236. Nellen JF, Smulders YM, Frissen PH, et al. Hypovitaminosis D in immigrant women: slow to be diagnosed. BMJ 1996; 312: 570-572. Gannage-Yared MH, Chemali R, Yaacoub N, et al. Hypovitaminosis D in a sunny country: relation to lifestyle and bone markers. J Bone Miner Res 2000; 15: 1856-1862. Daaboul J, Sanderson S, Kristensen K, Kitson H. Vitamin D deficiency in pregnant and breast-feeding women and their infants. J Perinatol 1997; 17: 10-14. Ahmed I, Atiq M, Iqbal J, et al. Vitamin D deficiency rickets in breast-fed infants presenting with hypocalcaemic seizures. Acta Paediatr 1995; 84: 941-942. Hoogenboezem T, Degenhart HJ, de Muinck Keizer-Schrama SM, et al. Vitamin D metabolism in breast-fed infants and their mothers. Pediatr Res 1989; 25: 623-628. Makin HLJ, Seamark DA, Trafford DJH. Vitamin D and its metabolites in human breast milk. Arch Dis Child 1983; 58: 750-753. (Received 23 Aug 2000, accepted 2 May 2001) Authors' details Department of Paediatrics, Monash University, Monash Medical Centre, Melbourne, VIC. Josephine M Nozza, FRACP, Paediatric Emergency Fellow, Children's Program. Christine P Rodda, PhD, FRACP, Senior Lecturer, Monash University, and Head of Paediatric Endocrinology and Diabetes. Reprints will not be available from the authors. Correspondence: Dr C P Rodda, Department of Paediatrics, Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168. c.roddaATsouthernhealth.org.au Make a comment 1: Serum biochemical profile at presentation in children with vitamin D deficiency rickets, by age Calcium Phosphorus Alkaline phosphatase >350U/L Parathyroid hormone >6.8pmol/L Age No. of children 16/17 8/17 16/16 13/13 Mean (95% CI) 1.53 (1.363-1.697) 1.54 (1.205-1.875) 1108 (853.5-1362.5) 40.2 (17.3-63.1) Age >9 months No. of children 14/38 19/37 35/38 21/25 Mean (95% CI) 2.08 (1.954-2.206) 1.31 (1.176-1.444) 1165 (890.8-1439.2) 29.54 (18.36-40.72) Total no. of children 30/55 27/54* 51/54* 34/38* Overall range 1.0-2.6mmol/L 0.55-3.07mmol/L 300-4042U/L 4.0-175pmol/L Reference ranges: calcium (2.1-2.6 mmol/L); phosphorus (1.3-2.3 mmol/L); alkaline phosphatase (100-350 U/L); and parathyroid hormone (1.0-6.8 pmol/L). *Some children did not have phosphorus, alkaline phosphatase, or parathyroid hormone analysed. Back to text 2: Clinical features at presentation of the 55 children* with vitamin D deficiency rickets Delayed walking 20 Leg bowing 14 Seizures 12 Failure to thrive 9 Incidental finding (detected on chest x-ray or routine biochemistry) 6 Bone pain 4 Tetany/carpopedal spasm 2 Short stature 1 Stiff hips 1 Pathological fracture 1 Sibling with rickets 1 *Some children presented with more than one symptom. Back to text 3: Age, sex, country of maternal origin, and serum 25-hydroxyvitamin D3 (25 OHD3) levels (children and mothers) of 31 children with rickets whose mothers were also assessed for vitamin D deficiency 25 OHD3 level Age of child (months) and sex Country of maternal origin Child Mother 11 days M India 24 4 F Sri Lanka 17 25 4 M Italy 19 5 M Somalia 9 9.3 6 M Somalia 6 13 6 M Turkey 7 11 8 M Sri Lanka 23 8 M Middle East 9 9* M Iraq* 6 9* F Iraq* 11 M Africa —† 5 11 M Egypt 8 11 M Ethiopia 20 12 M Africa —† 20 13 F Lebanon —† 39 14 F Sri Lanka 7 20 14 F Australia 25 16 M Ethiopia —† 16 M Somalia nd 55‡ 16 F Lebanon 12 16 M Ethiopia 15 17 17 F Turkey nd 45‡ 17 M Ethiopia 5.5 17 M Italy 36 12 17 F Lebanon 25 18 M Zaire 22 40 18 M Pakistan 9 12 18 F India 14 20 M Zaire 22 40 25 F India 22 47 27 M Sudan 17 10 30 M Kenya 26 *Twins. †Vitamin D levels measured after commencement of treatment. ‡Maternal levels measured after education regarding sun exposure/diet nd=not done. Reference range, 25-108nmol/L Back to text

Josephine M Nozza · Christine P Rodda

Diagnostic Dilemmas Contaminated medication precipitating hypoglycaemia Adrian M Goudie and Joey M Kaye We report a case of hypoglycaemia in a patient with diet-controlled type 2 diabetes. Enquiries and investigations led to a diagnosis of sulfonylurea poisoning from contaminated herbal medication. MJA 2001; 175: 256-257 Clinical record - Discussion - Conclusion - References - Authors' details - - - More articles on Endocrinology Many Australians use herbal or alternative medication,1 often without informing their doctors. Side effects and interactions from these medications, including problems with contaminants, can occur, as illustrated by the case described here. Clinical record A 56-year-old Indonesian tourist presented to our emergency department in September 1999. On arrival, he appeared unable to speak English, so his history was obtained from his wife and ambulance personnel. He had arrived from Jakarta three days previously and had been vaguely unwell with "flu" for the last few days. At 11:30 pm he had awoken confused and agitated, possibly with chest pain. On arrival of the ambulance, his capillary blood glucose level was 2.1 mmol/L, so he was given 1 mg of glucagon intramuscularly. During transfer he was given aspirin (300 mg) and isosorbide mononitrate (10 mg, sublingually). His agitation and confusion settled during the transfer to hospital. On arrival at the hospital his capillary blood glucose level was 4.3 mmol/L. He was speaking Indonesian and was alert and cooperative. He reported having diet-controlled non-insulin-dependent (type 2) diabetes mellitus, ischaemic heart disease (with coronary artery bypass surgery 12 years previously), hypertension and hypercholesterolaemia. He was taking amlodipine, aspirin and atorvastatin, but denied taking any medications for his diabetes. He was given some sandwiches while the history was being taken and an examination was performed. At 2:45 pm his capillary blood glucose level was found to be 2.1 mmol/L. Shortly after this, the laboratory rang to give a formal venous glucose concentration result of 2.9 mmol/L for a sample taken at 1:48 pm. Despite being given sugary drinks, then increasing dextrose infusions and intermittent boluses of dextrose, each time his blood sugar was retested it was found to be low (see Box). A 50 mL per hour infusion of 50% dextrose was required to prevent hypoglycaemia. After the first bolus of 50% dextrose it was discovered that he could speak English fluently. He confirmed his diabetes was diet-controlled and that he was not taking any hypoglycaemic medications. The lack of any obvious cause for the hypoglycaemia prompted us to consider rarer causes, and, in response to direct questioning about herbal and traditional medication, he admitted to taking a preparation called "ZhenQi" for his diabetes, which he had purchased in Malaysia. He had been taking this medication for the last five years, initially taking five capsules per day, then having increased the dose to three capsules three times daily (with no dose alteration) for the last two years. The label on the bottle of this preparation listed the ingredients as ginseng, pearl, ram's horn, bark and "frog extract". He had started a new bottle of the preparation recently, coinciding with the onset of the "flu"-like symptoms (lethargy, feeling cold and tremor). Serum taken during the period of hypoglycaemia (when his glucose level was 2.9 mmol/L) had elevated levels of C-peptide (3.80 nmol/L; normal range, 0.20-0.90 nmol/L) and insulin (50 mU/L; normal range, 3-26 mU/L). Analysis of the herbal medication capsules by gas chromatography and mass spectrometry (by PathCentre, Perth, Western Australia) revealed the presence of glibenclamide. Infusions of 50% dextrose and potassium were required for 20 hours, then reduced gradually over the next 24 hours. The serum insulin level had returned to normal 36 hours after admission. He was discharged on Day 3. Discussion Hypoglycaemia is a common reason for patients with diabetes to present to emergency departments, and is usually the result of an imbalance between oral intake, physical activity and the effects of medication.2 However, hypoglycaemia occurring in a patient with diet-controlled type 2 diabetes is unusual, and raises the possibility of one of the many rarer causes of hypoglycaemia. The diagnosis of hypoglycaemia rests on three criteria (Whipple's triad) of plasma hypoglycaemia, symptoms attributable to a low blood sugar level and resolution of symptoms with correction of the hypoglycaemia.3 There are many causes of hypoglycaemia,2-4 but it is most commonly the result of an excess of either insulin or oral hypoglycaemic medications combined with reduced sugar intake or increased activity.2 Our patient's initial claims that he was not taking any medications for glycaemic control led to a search for other causes. Although he had been taking the same dose of the herbal preparation for two years, we felt that it was the most likely cause of the hypoglycaemia. Insulin and C-peptide levels were therefore measured and both were elevated, indicating an endogenous insulin source as the cause. This can result from either an insulinoma, sulfonylurea drug (which stimulates the pancreatic islet cells to release insulin), drugs with a sulfonylurea-like action (eg, quinine)4 or autoimmune hypoglycaemia. Insulinomas usually cause semiautonomous release of insulin, resulting in fasting hypoglycaemia. In response to meals these tumours usually respond subnormally, so that postprandial glucose levels are normal or even mildly elevated,2 although postprandial hypoglycaemia can occur. This patient's persistent hypoglycaemia despite food would therefore be atypical for an insulinoma. However, computed tomography (CT) of the abdomen was performed (prior to the insulin and C-peptide levels being available) to exclude this possibility, or that of a large sarcoma (which can cause hypoglycaemia because of insulin-like growth-factor II release) — no pancreatic or intra-abdominal masses were detected. Insulinomas may be too small to be seen on CT scans5 and further investigation with endoscopic ultrasound was considered, if no other cause for the hypoglycaemia became apparent. Sulfonylurea overdose can lead to profound hypoglycaemia, with chlorpropamide and glibenclamide being the agents most frequently implicated.6 Both prolonged and recurrent hypoglycaemia must be expected. Potassium supplementation is often required. Dextrose infusions are usually sufficient, but can stimulate further insulin release from the sulfonylurea-primed beta cells. Octreotide and diazoxide both inhibit insulin release and have been recommended for treating severe poisoning refractory to dextrose.7,8 Steroids and glucagon have also been recommended, but are thought to be less effective.8 In our patient, analysis of the herbal medication capsules revealed the presence of glibenclamide. Plasma tests to screen for sulfonylureas are available and can be used to detect inadvertent or surreptitious ingestion.9 The use of herbal and alternative medicine is becoming more common, and it has been estimated that almost half of the Australian population use some form of such products within a 12-month period.1 Many patients do not inform their doctors that they take them.10 It is therefore important to ask directly whether patients are taking such substances. Numerous herbal preparations have been shown to affect blood glucose levels through various mechanisms, although they are usually limited by toxicity or relative lack of efficacy compared with standard medications.11,12 The lack of standardisation of ingredients and preparation also causes problems.13 Contamination with "conventional" medications has been reported to cause adverse effects.14,15 In this case, we felt it most likely that the sulfonylurea had been added to the herbal ingredients in the preparation of the capsules. Conclusion The cause of hypoglycaemia, commonly seen in emergency departments, is usually obvious. When it is not, then rarer causes and factitious disorders must be considered. The use of herbal and alternative medications must be considered and specifically asked about in all patients. Competing interests: None. References MacLennan AH, Wilson DH, Taylor AW. Prevalence and cost of alternative medicine in Australia. Lancet 1996; 347: 569-573. Turner RC. Hypoglycemia. In: Weatherall DJ, Ledingham JGG, Warrell DA, editors. Oxford textbook of medicine. 3rd ed. Oxford: Oxford University Press; 1996: 1505-1502. Foster DW, Rubenstein AH. Chapter 335: Hypoglycemia. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, editors. Harrison's principles of internal medicine. 14th ed. CD-ROM. New York: McGraw Hill; 1998. Marks V, Teal JD. Drug-induced hypoglycaemia. Endocrinol Metab Clin North Am 1999; 28: 555-577. Ardengh JC, Rosenbaum P, Ganc AJ, et al. Role of EUS in the preoperative localization of insulinomas compared with spiral CT. Gastrointest Endosc 2000; 51: 552-555. Seltzer H. Drug-induced hypoglycaemia: a review of 1418 cases. Endocrinol Metab Clin North Am 1989; 18: 168-171. Boyle PJ, Justice K, Krentz AJ, et al. Octreotide reverses hyperinsulinaemia and prevents hypoglycaemia induced by sulfonylurea overdoses. J Clin Endocrinol Metab 1993; 76: 752-756. Palatnick W, Meatherall RC, Tenenbein M. Clinical spectrum of sulfonylurea overdose and experience with diazoxide therapy. Arch Intern Med 1991; 151: 1859-1862. Shenfield GM, Boutagy JS, Webb C. A screening test for detecting sulfonylureas in plasma. Ther Drug Monit 1990; 12: 393-397. Kristoffersen SS, Atkin PA, Shenfield GM. Uptake of alternative medicine [letter]. Lancet 1996; 347: 972. Bailey CJ, Day C. Traditional plant medicines as treatments for diabetes. Diabetes Care 1989; 12: 553-563. Miller LG. Herbal medicinals. Arch Intern Med 1998; 158: 2200-2211. Shaw D, Leon C, Kolev S, Murray V. Traditional remedies and food supplements. Drug Safety 1997; 17: 342-356. Rios CA, Sahud MA. Agranulocytosis caused by Chinese herbal medicines. Dangers of medications containing aminopyrine and phenylbutazone. JAMA 1975; 231: 352-355. Bury RW, Fullifaw RO, Barraclough D, et al. Problems with herbal medicines. Med J Aust 1987; 146: 324-325. (Received 30 Mar, accepted 21 Jun, 2001) Authors' details Royal Perth Hospital, Perth, WA. Adrian M Goudie, MB BS, FACEM, Emergency Department Consultant; Joey M Kaye, MB BS, Endocrinology Registrar (currently, Research Fellow, University Research Centre for Neuroendocrinology, Bristol Royal Infirmary, Bristol, UK). Reprints will not be available from the authors. Correspondence: Dr A M Goudie, Royal Perth Hospital, Box X2213, GPO, Perth, WA 6847. adriangoudieATyahoo.com.au Make a comment Back to text

Adrian M Goudie · Joey M Kaye

Position Statement Anticoagulation in pregnancy and the puerperium A Working Group on behalf of the Obstetric Medicine Group of Australasia MJA 2001; 175: 258-263 Abstract - Management and prophylaxis of venous thromboembolism in pregnancy and the puerperium - Acute venous thromboembolism - Prophylaxis of venous thromboembolism - General - Previous thromboembolism - Previous single VTE and no recognised thrombophilia - Previous recurrent VTE or idiopathic VTE - Familial thrombophilia - Hyperhomocysteinaemia - Antiphospholipid syndrome and VTE - Management and prophylaxis of obstetric problems associated with uteroplacental thrombosis - References - Authors' details - - More articles on Obstetrics & gynaecology and women's health Abstract For the management of acute thrombotic events in pregnancy therapeutic doses of low molecular weight heparins (LMWH) may be used, unless the shorter half-life of intravenous unfractionated heparin (UH) and predictable reversibility by protamine are important. Treatment should be continued up until delivery and into the puerperium. Pregnant women who have had an acute thrombotic event should be delivered by a specialist team. In the case of recent thrombosis, delivery should be planned and the time during which anticoagulation therapy is ceased around the time of delivery should be minimised. Therapeutic doses of LMWH contraindicate the use of regional anaesthesia, and a switch to intravenous UH before delivery may allow greater flexibility in this regard. Prophylactic doses of LMWH can be used to reduce the risk of recurrent thromboembolic events in pregnancy. The regimen used will depend on the previous history, the family history and the presence of risk factors, including the genetic and acquired causes of thrombophilia. Women with mechanical heart valves are at high risk during pregnancy and require therapeutic anticoagulation throughout pregnancy under the direction of experienced specialists. Low-dose aspirin can reduce the risk of recurrent pre-eclampsia by about 15%, but the role of UH and LMWH in the prevention of recurrent miscarriage or obstetric complications associated with uteroplacental insufficiency is still uncertain. Low molecular weight heparins (LMWH) are being used increasingly as standard treatment for venous thrombosis, replacing unfractionated heparin (UH) for both therapeutic and prophylactic anticoagulation. Compared with UH, LMWH have increased bioavailability and a longer half-life. They also have the benefits of ease of administration, often as a single daily dose, have reduced requirements for monitoring, and are associated with less heparin-induced thrombocytopenia, reduced bleeding complications and improved patient acceptability.1Heparins do not cross the placenta, whereas warfarin does.2,3 By contrast, warfarin is teratogenic between six and 12 weeks' gestation, and may cause fetal and neonatal bleeding if used during the second or third trimester. Except perhaps in women with mechanical heart valves, there is general agreement that UH or LMWH should be substituted for warfarin as soon as pregnancy is diagnosed. Long-term treatment with UH carries risks of maternal osteoporosis4-6 and heparin-induced thrombocytopenia. Consistent, long term therapeutic anticoagulation can be hard to achieve with subcutaneous UH, because of low bioavailability and the changing anticoagulant response to UH as pregnancy progresses, often requiring close laboratory monitoring. LMWH require much less monitoring and appear to carry a smaller risk of heparin-induced thrombocytopenia, bleeding, and probably osteoporosis.7-9 Data on the effectiveness and safety of LMWH in pregnancy are limited but systematic reviews are becoming available.10 Given the convenience of LMWH and doctors' increasing familiarity with their use, there is growing opinion that LMWH have a role in pregnancy in preference to UH. In this position paper we summarise current views and make consensus recommendations for anticoagulation in pregnancy and the puerperium. The consensus process followed for this article is summarised in Box 1. Management and prophylaxis of venous thromboembolism in pregnancy and the puerperium Acute venous thromboembolism Antenatal management: Clinical trials in non-pregnant patients show that LMWH are at least as effective and safe as UH in the initial management of acute proximal or calf deep venous thrombosis (DVT).1 Recurrence of thromboembolism is reduced by ongoing warfarin therapy and, in the case of proximal DVT, treatment should be continued for at least six months (C1). The standard initial treatment for pulmonary embolism, whether during pregnancy or not, remains intravenous UH (C2). For an antenatal DVT, treatment should start with a LMWH at the therapeutic dose recommended by the manufacturers9(Box 2) (C1). Intravenous UH may be preferred in situations where its short half-life and predictable reversibility by protamine sulfate are important (eg, when delivery or surgery may be imminent). Calf DVT should be treated in the same way as proximal DVT in pregnancy because of ongoing hypercoagulability during pregnancy (C2). If intravenous UH is used for the initial treatment of pulmonary embolism, therapeutic doses of LMWH may be commenced once the patient is haemodynamically stable (C1). Anticoagulation therapy should then be maintained until delivery (C1). It is generally recommended that therapeutic doses of UH or LMWH be continued throughout pregnancy.9,11,12 In practice, some clinicians change to a prophylactic dose of LMWH after 12 weeks of therapy if the woman is still pregnant, and continue with this dose until labour (Box 2) (C3). The rationale for this approach includes a declining risk of recurrence with time after acute venous thromboembolism (VTE),13 a desire to reduce osteoporosis associated with LMWH, and the suggestion from small trials in non-pregnant patients that lower prophylactic or intermediate doses of LMWH may be as effective as warfarin in preventing secondary recurrence of VTE.14-16 The safety of such a reduction of LMWH dose before 12 weeks after acute VTE in pregnancy needs to be established in clinical trials. Monitoring: There is no need to use an anti-factor Xa assay to monitor either therapeutic or prophylactic doses of LMWH (C2). Therapy with UH can be monitored and managed according to the activated partial thromboplastin time (APTT). Management of labour and delivery: Women requiring therapeutic anticoagulation should be counselled before delivery, which should be planned under the care of a specialist team (C1). Elective delivery allows for dose adjustment to minimise the opposing risks of bleeding at delivery and of further thrombosis.13 Vaginal delivery is preferable, as there is less risk of haemorrhage than with caesarean section. Delivery by caesarean section should be determined on the basis of obstetric indications (C1). The use of regional anaesthesia requires special consideration, and is outlined in Box 3. The intensity of anticoagulation therapy required during delivery depends on how recently the VTE occurred. If within the last month, each day without anticoagulation therapy is associated with a 1% absolute increase in the risk of recurrence.13 It is therefore important to minimise the time off anticoagulation. Intravenous UH should be substituted for LMWH 24-36 hours before obstetric intervention, aiming to maintain the APTT at 1.5-2 times baseline. After induction, UH therapy is ceased once labour is established, allowing the APTT to return to normal, usually within 4-6 hours. Women requiring elective caesarean section should cease UH therapy six hours before surgery to allow for the full range of obstetric and anaesthetic options (C1). If the VTE occurred between one and three months previously, therapeutic LMWH can be reduced to a prophylactic dose for 24-48 hours and labour can then be induced. The last dose of LMWH is given the night before induction. In women whose cervical assessment suggests that labour is likely to be established within a few hours of induction, the last dose of LMWH before induction may be withheld (C2). Women who have had a VTE more than three months previously and who are still receiving a therapeutic dose of LMWH can be switched to a prophylactic dose at 38 weeks' gestation, allowing spontaneous labour to occur. Again, LMWH are withheld at the onset of labour (C2). Alternatively, if a woman wishes to be assured of access to epidural anaesthesia, induction of labour can be offered, with the last dose of LMWH on the day before the day of induction (C2). Anti-embolism stockings, compression devices and electrical calf stimulators may be used and continued postpartum, especially if caesarean delivery is undertaken (C1). In all women in whom anticoagulants have been used, the third stage of labour should be managed actively with oxytocic therapy and controlled cord traction to minimise the risk of postpartum haemorrhage (C1). Postpartum management: Postpartum, anticoagulation therapy is usually recommenced at the same intensity as that used antenatally. Prophylactic doses can be recommenced within 2-6 hours of both vaginal and caesarean deliveries (C1). This may be prophylactic doses of LMWH or low-dose (12 000 U/24 h) UH infusion, if rapid reversal of anticoagulation may be required. Therapeutic doses of UH or LMWH may be reintroduced 24 hours after vaginal delivery (C2). Caution should be exercised in recommencing therapeutic doses of LMWH earlier than 24 hours after operative delivery because of the risk of surgical bleeding, but most women can be receiving therapeutic doses by 36-48 hours after caesarean section (C1). Warfarin therapy can then be initiated and, once therapeutic levels have been achieved, continued in place of LMWH to complete the six months of therapy and for at least six weeks postpartum. Neither medication contraindicates breastfeeding (C1). Prophylaxis of venous thromboembolism General VTE remains a major cause of maternal mortality in Australia, the United Kingdom and in the United States, occurring at a rate of approximately one death per 100 000 maternities.11,12,18 The rate is much higher in older women; in the UK, women aged over 39 years had a mortality rate of 1 per 3300 pregnancies.19 VTE can occur at any time during pregnancy; its prevalence is approximately equally distributed between the three trimesters.20 Although two-thirds of events occur antenatally, the day-by-day risk is greatest in the first weeks after delivery.20Major known risk factors for VTE in pregnancy and postpartum include caesarean section (particularly in labour), obesity, prolonged bed rest and immobility, pre-eclampsia, nephrotic syndrome, current infection and other recent surgery, in addition to previous VTE and thrombophilia. These risk factors often coexist and reinforce each other. A risk-assessment profile may be constructed, as suggested in the consensus report from the Royal College of Obstetricians and Gynaecologists,21 which recommends that: all "at risk" women should be monitored for symptoms and signs of VTE during the first week postpartum; hydration should be maintained and early mobilisation encouraged; graduated compression stockings with or without calf stimulation should be used during and after caesarean section in women at moderate risk (one or two risk factors); in women at high risk (three or more risk factors), LMWH or UH prophylaxis should be used and continued for at least five days. The efficacy or benefit of these interventions is unknown, as no high grade evidence is available. Previous thromboembolism In women who have had previous VTE, the risk of recurrence will be influenced by a number of factors, including whether the index event was spontaneous or provoked, the presence or absence of a family history of VTE, the presence of a known thrombophilia, or whether there has been more than one episode of VTE. The decision as to whether VTE prophylaxis is required throughout pregnancy or only postpartum may be based on this information (Box 4).22Women requiring prophylaxis during pregnancy can be managed with low-dose LMWH (Box 2). They can then be allowed to come into spontaneous labour (C2). LMWH are withheld at the onset of labour (C2). Alternatively, if such a woman wishes to be assured of access to regional anaesthesia, induction of labour can be offered, with the last dose of LMWH on the day before the day of induction (Box 3) (C2). Previous single VTE and no recognised thrombophilia Both earlier and more recent cohort data suggest that most pregnant women with a past history of a single precipitated thrombotic event in or out of pregnancy, or associated with the combined oral contraceptive pill, and who have no underlying thrombophilia, can be safely managed by careful observation before delivery and postpartum thromboprophylaxis for six weeks23 (C2). Previous recurrent VTE or idiopathic VTE Women who have either recurrent VTE, previous idiopathic VTE, or a previous VTE and a strong family history of VTE but with no demonstrated cause for thrombophilia, may be given thromboprophylaxis throughout pregnancy and for six weeks postpartum23,24 (C1). Familial thrombophilia Thromboembolism is a multifactorial disease, in many cases developing as a result of a thrombotic tendency (a thrombophilia) interacting with other factors, such as pregnancy.25,26 Situations in which such a thrombophilia may require consideration during pregnancy are: previous personal thromboembolic disease and known thrombophilia; no previous VTE, but a strong family history (ie, one or more first-degree relatives affected) and known thrombophilia; no previous VTE, strong family history, no previous investigations; no previous VTE, weak family history (ie, incidental finding of thrombophilia in a family member); and no personal or family history of VTE, but known thrombophilia detected after screening (eg, after obstetric complications or before starting to take the combined oral contraceptive pill). The known causes of familial thromboembolism differ in their risk of associated thrombosis.27 The prevalence of such thrombophilic disorders varies between populations.28 A combination of any two or more inherited factors substantially increases the risk of thromboembolism. Box 4 summarises the risk profiles of the various genetic thrombophilias and offers guidelines for therapy. Box 5 describes management during pregnancy of medical problems requiring anticoagulation outside pregnancy. Hyperhomocysteinaemia In women with a previous history of VTE and hyperhomocysteinaemia, it may be prudent to reduce plasma homocysteine concentrations by folate supplementation throughout pregnancy, in addition to other thromboprophylaxis (C2). Antiphospholipid syndrome and VTE The presence of a lupus anticoagulant or of moderately to strongly positive titres of anticardiolipin antibody (ACA) is a strong risk factor for recurrent VTE, especially in pregnancy. Suggestions for treatment are shown in Box 4. Unless there is an associated history of poor obstetric outcome (see below), low-dose aspirin therapy need not be added (C2). On the other hand, it is contentious whether women with a positive lupus anticoagulant with or without ACA with no previous history of VTE (eg, women with systemic lupus erythematosus) require any prophylactic treatment at all during pregnancy. Low-dose aspirin may be a reasonable option for such women (C1). Management and prophylaxis of obstetric problems associated with uteroplacental thrombosis A common pathophysiological link between various poor pregnancy outcomes, including recurrent miscarriage, stillbirth, placental abruption, fetal growth restriction and pre-eclampsia, is thrombosis in the uteroplacental circulation. Antiplatelet agents (especially low-dose aspirin) have been trialled, particularly for preventing pre-eclampsia. A recent systematic review has shown a 15% reduction in the incidence of recurrent pre-eclampsia when low-dose aspirin is used, less benefit for the prevention of preterm birth and no benefit for the prevention of fetal growth restriction.35 Whether LMWH or UH can be used safely and more effectively than just aspirin in placental vasculopathy, with or without thrombophilia, is currently under investigation. Only in the case of recurrent miscarriage associated with the antiphospholipid syndrome has the addition of UH to aspirin been shown to be beneficial.36 A number of small cohort studies in women with previous obstetric complications who were treated with LMWH showed a good outcome, but whether the outcome was related to the use of LMWH is uncertain.37,38While awaiting the results of further studies, and given the small numbers of affected women, no specific treatment recommendations can be made. We encourage clinicians to refer such patients to centres where randomised controlled trials are being carried out or where cohort studies are under way. Competing interests: The authors are grateful to Pharmacia Upjohn for an unrestricted financial grant towards the costs involved in the preparation of this article, although the company did not contribute in any way either to the analysis or to the recommendations. There are no other known conflicts of interest. Future research questions The working party identified further areas for research. These include: Comparison of LMWH versus intravenous UH in acute DVT and pulmonary embolism in pregnancy. High-dose versus low-dose LMWH therapy for secondary prophylaxis after acute DVT in pregnancy. The value of prospective blinded anti-Xa levels in the use of therapeutic LMWH in pregnancy. The timing, benefits and risks of any dose adjustment of LMWH/UH, particularly peripartum. Controlled longitudinal studies of bone density and fracture rates in women using long-term LMWH. Prevention of pregnancy-associated VTE: the risks and benefits of LMWH thromboprophylaxis during pregnancy and postpartum for specific groups. Prevention of adverse pregnancy complications related to placental insufficiency. Randomised studies to determine the efficacy of LMWH in improving subsequent pregnancy outcome in women with specific pregnancy complications and an underlying thrombophilia. A register of women being treated with anticoagulants during pregnancy. A register to determine the clinical significance of thrombophilias in particular patient groups. References Weitz J. Drug therapy: low molecular weight heparins. N Engl J Med 1997; 337: 688-698. Flessa H, Kapstrom AB, Glueck HI, Will JJ. Placental transport of heparin. Am J Obstet Gynecol 1965; 934: 570-573. Forestier F, Sole Y, Aiach M, et al. Absence of transplacental passage of fragmin (Kabi) during the second and the third trimesters of pregnancy. Thromb Haemostas 1992; 67: 180-181. Dahlman TC, Sjoberg HE, Ringertz H. Bone mineral density during long-term prophylaxis with heparin in pregnancy. Am J Obstet Gynecol 1994; 170: 1315-1320. Douketis JD, Ginsberg JS, Burrows RF, et al. The effects of long-term heparin therapy during pregnancy on bone density — a prospective matched cohort study. Thromb Haemost 1996; 75: 254-257. Barbour LA, Kick SD, Steiner JF, et al. A prospective study of heparin-induced osteoporosis in pregnancy using bone densitometry. Am J Obstet Gynecol 1994; 170: 862-869. Nelson-Piercy C. Heparin-induced osteoporosis in pregnancy. Lupus 1997; 6: 500-504. Farquharson RG. Heparin, osteoporosis and pregnancy. Br J Hosp Med 1997; 58: 205-207. Ginsberg J, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 2001; 199: 122S-131S. Sanson BJ, Lensing AW, Prins MH, et al. Safety of low molecular weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-672. Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999; 353: 1258-1265. Toglia M, Weg J. Current concepts: venous thromboembolism during pregnancy. N Engl J Med 1996; 335: 108-114. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997; 336: 1506-1511. Pini M, Aiello S, Manotti C, et al. Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. Thromb Haemost 1994; 72: 191-197. Gonzalez-Fajardo J, Arreba E, Castrodeza J, Perez J, et al. Venographic comparison of subcutaneous low-molecular weight heparin with oral anticoagulant therapy in the long-term treatment of deep venous thrombosis. J Vasc Surg 1999; 30: 283-292. Das S, Cohen A, Edmonson R, et al. Low molecular weight heparin versus warfarin for prevention of recurrent venous thromboembolism: a randomized trial. World J Surg 1996; 20: 521-527. Tryba M. European practice guidelines: thromboembolism prophylaxis and regional anesthesia. Regional Anesthes Pain Med 1998; 23 (6 Suppl 2): 178-182. Maternal mortality committee. Maternal deaths in Australia 1991-1993. Canberra: NHMRC, 1998. Department of Health. Why mothers die. Report on confidential enquiries into maternal deaths in the United Kingdom 1994-1996. London: The Stationery Office; 1998. Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv 1999; 54: 265-271. Royal College of Obstetricians and Gynaecologists. Report of the RCOG Working Party on prophylaxis against thromboembolism in gynaecology and obstetrics. London: RCOG, 1995. McColl MD, Walker ID, Greer IA. The role of inherited thrombophilia in venous thromboembolism associated with pregnancy. Br J Obstet Gynaecol 1999; 106: 756-766. Brill-Edwards P, Ginsberg J, Gent M, et al. Safety of withholding antepartum heparin in women with a previous episode of venous thromboembolism. N Engl J Med 2000; 343: 1439-1444. Letsky EA. Peripartum prophylaxis of thrombo-embolism. Baillieres Clin Obstet Gynaecol 1997; 11: 523-543. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-1173. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-916. Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000; 342: 374-380. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-1231. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves — a systematic review of the literature. Arch Intern Med 2000; 160: 191-196. Arnaout M, Kazma H, Khalil A, et al. Is there a safe anticoagulation protocol for pregnant women with prosthetic valves? Clin Exp Obstet Gynecol 1998; 25: 101-104. Elkayam U. Pregnancy through a prosthetic heart valve. J Am Coll Cardiol 1999; 33: 1642-1645. Lee LH, Liauw PCY, Ng ASH. Low molecular weight heparin for thromboprophylaxis during pregnancy in 2 patients with mechanical mitral valve replacement. Thromb Haemost 1996; 76: 628-630. Sadler L, McCowan L, White H, et al. Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves. Br J Obstet Gynaecol 2000; 107: 245-253. Rowan J, McCowan L, Raudkivi P, North R. Enoxaparin treatment in women with mechanical heart valves during pregnancy. Am J Obstet Gynecol. In press. Knight M, Duley L, Henderson Smart DJ, King JF. Antiplatelet agents for preventing and treating pre-eclampsia. Cochrane Database Syst Rev 2000; 2. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314: 253-257. Brenner B, Hoffman R, Blumenfeld Z, et al. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83: 693-697. Riyazi N, Leeda M, de Vries J, et al . Low-molecular-weight heparin combined with aspirin in pregnant women with thrombophilia and a history of preeclampsia or fetal growth restriction: a preliminary study. Eur J Obstet Gynecol Reprod Biol 1998; 80: 49-54. The authors of the Position Statement are listed below Authors' details Department of Obstetrics, University of Adelaide, Women's and Children's Hospital, North Adelaide, SA. William M Hague, FRCP, FRCOG, Senior Physician in Obstetric Medicine and Clinical Senior Lecturer. National Women's Hospital, Auckland, New Zealand Robyn A North, PhD, FRACP, Associate Professor in Obstetric Medicine. Flinders Medical Centre, Bedford Park, SA. Alexander S Gallus, FRCPA, FRACP, Haematologist and Professor. King Edward Memorial Hospital, Subiaco, WA. Barry N J Walters, MB BS, FRACP, Physician in Obstetric Medicine and Clinical Associate Professor, Department of Obstetrics and Gynaecology, University of Western Australia. Christopher Orlikowski, MB BS, FANZCA, Anaesthetist. Monash University, Monash Medical Centre, Melbourne, VIC. Robert F Burrows, FACOG, FRANZCOG, Professor of Maternal-Fetal Medicine. Mater Mothers' Hospital, South Brisbane, QLD Robert B Cincotta, FRANZCOG, CMFM, Specialist in Maternal-Fetal Medicine. North Western Adelaide Health Service, Adelaide, SA. Gustaaf A Dekker, PhD, FRANZCOG, Professor of Obstetrics and Gynaecology. Mercy Hospital for Women, East Melbourne, VIC. John R Higgins, MD, FRANZCOG, Senior Lecturer in Obstetrics and Gynaecology (currently, Professor of Obstetrics and Gynaecology, University College, Cork, Ireland). Royal Hospital for Women, Sydney, NSW. Sandra A Lowe, MD, FRACP, Physician in Obstetric Medicine. Royal North Shore Hospital, Sydney, NSW. Jonathan M Morris, MD, FRANZCOG, Senior Lecturer in Obstetrics and Gynaecology. Nepean Hospital, Sydney, NSW. Michael J Peek, PhD, FRANZCOG, Professor of Obstetrics and Gynaecology. Reprints will not be available from the authors. Correspondence: Dr W M Hague, Department of Obstetrics, Women's and Children's Hospital, North Adelaide, SA 5006. bill.hagueATadelaide.edu.au Make a comment 1: Consensus process The authors of this position statement are members of the Obstetric Medicine Group of Australasia (OMGA), with a particular clinical and research interest in managing pregnant women with thromboembolic problems. The authors were all members of the working party, and include six obstetricians, four obstetric physicians, an obstetric anaesthetist and a clinical haematologist. We met collectively in October 1999 to discuss the broad issues of the use of low molecular weight heparins in pregnancy before producing a draft document; this was subsequently modified by written comments and refined at teleconferences in May, June and September 2000. The position statement is a consensus statement inasmuch as there is little high-grade evidence from either randomised trials or other cohort studies on which to make recommendations, especially for management. Our recommendations have been annotated to reflect the degree of agreement among us as follows: C1 Complete consensus; C2 Near-complete consensus (nine or more of the 12 authors); and C3 No consensus. Back to text 2: Doses of low molecular weight heparins Low molecular weight heparin Therapeutic dose Prophylactic dose Dalteparin (Fragmin) 100U/kg twice daily 5000U daily Enoxaparin (Clexane) 1 mg/kg twice daily 40mg daily or 1.5mg/kg daily Back to text 3: Suggested guidelines for regional anaesthesia and levels of consensus (Box 1) Regional anaesthesia (epidural or spinal block) is contraindicated during anticoagulation therapy because of the increased (although unquantified) risks of spinal haematoma17 (C1). If a regional anaesthetic is desired in women who require anticoagulation therapy, an elective delivery will allow for a planned reduction in dose or a change to intravenous unfractionated heparin (UH) (C1). Therapeutic subcutaneous injections of low molecular weight heparins (LMWH) or UH should be ceased at least 24 hours, and preferably 36 hours, before regional anaesthesia (epidural or spinal block) (C1). Intravenous UH (used to permit a rapid return of the APTT to normal after cessation of the infusion) should be discontinued at least six hours, and preferably 12 hours, before regional anaesthesia (C1). In women receiving prophylactic LMWH, an interval of more than 20 hours from the last dose should allow the placement of a regional block with minimal risk of complications (C2). A normal activated partial thromboplastin time (APTT) does not ensure minimal anticoagulant effect of LMWH, and the platelet count should be determined to exclude heparin-induced thrombocytopenia (C2). If caesarean section is being undertaken, further doses of LMWH should be delayed for at least four hours after placement of an uncomplicated regional block, and longer if the regional block has been complicated (C1). Low-dose LMWH therapy can be continued after delivery if there have been no complications in the siting of the regional block.17 An epidural catheter can be removed 12-20 hours after a prophylactic dose of LMWH, and the next injection should be delayed by at least four hours after removal (C1). Women should be closely monitored postpartum for any symptoms or signs of spinal haematoma, in particular for numbness and weakness in the lower limbs, severe back pain, and bladder or bowel incontinence (C1). Back to text Box 4 consists of 4a, 4b, 4c, 4d. 4a: Suggested management guidelines and levels of consensus (see Box 1) Thromboprophylaxis against recurrent venous thromboembolism (VTE) in pregnant women with previous VTE and no identified thrombophilia, according to estimated pregnancy-related risk of thrombosis Single episode of VTE Thrombosis history Recurrent VTE Spontaneous Probable cause* Family history of VTE in one or more 1st degree relatives PrA (option ThA) (C2) PrA (C2) Negot (C2) No family history of VTE PrA (C1) Negot (C2) Nil (C2) *Risk factors present such as surgery, combined oral contraceptive pill. Back to text 4b: Anticoagulation to prevent venous thromboembolism (VTE) in pregnant women testing positive for lupus anticoagulant or anticardiolipin antibodies (ACA), according to estimated pregnancy-related risk of thrombosis Lupus anticoagulant and/or ACA IgG ACA IgG weak moderate-strong positive,* ACA Thrombosis history positive* IgM positive Recurrent VTE in pregnancy despite prophylaxis ThA (C1) ThA (C1) Recurrent VTE outside pregnancy ThA (C2) ThA (C2) Previous VTE PrA (C1) Negot (C1) No previous VTE Nil (C1) Nil (C1) *Based on the highest-ever titre measured in the individual patient. Back to text 4c: Preventing venous thromboembolism (VTE) in pregnant women with established thrombophilias, according to estimated pregnancy-related risk of thrombosis Thrombosis history Antithrombin deficiency (Very rare) Protein C deficiency (Rare) Protein S deficiency (Rare) FVL* or PGM† homozygous (Uncommon) FVL* or PGM† heterozygous (Common) Personal history of VTE independent of family history ThA (C2) PrA (C1) PrA (C1) PrA (C1) Negot (C1) Family history of VTE in one or more 1st degree relatives ThA/PrA (C3) PrA (C1) PrA (C1) PrA (C1) Negot (C1) Family history of VTE in a distant relative ThA/PrA (C3) PrA (C1) Negot (C1) Negot (C1) Nil (C1) No personal or family history of VTE ThA/PrA (C3) PrA (C1) Nil (C1) Nil (C1) Nil (C1) *G1691A mutation in the factor V gene [Factor V Leiden] causing activated protein C resistance; †G20210A mutation in the prothrombin (factor II) gene. Back to text 4d: Key to management recommendations ThA Therapeutic anticoagulation necessary throughout pregnancy and postpartum - very high risk (>20%). PrA Prophylaxis necessary throughout pregnancy and puerperium - high risk (10%-20%). Negot Need for prophylaxis negotiable on a case-by-case basis until further data become available - moderate risk (3%-10%). Nil Postpartum prophylaxis or no prophylaxis - low risk (3%). Back to text 5: Management during pregnancy of medical problems requiring anticoagulation therapy outside pregnancy (consensus levels are described in Box 1) Women with mechanical heart valves require therapeutic doses of anticoagulant medication throughout pregnancy to prevent valve thrombosis or maternal thromboembolic events9 (C1). Women with mechanical heart valves should be managed under joint subspecialty care (C1). The maternal benefits of warfarin (prevention of valve occlusion and systemic embolism) must be balanced against hazards to the fetus (congenital anomalies, intracranial haemorrhage and fetal loss).29 Unfractionated heparin (UH) and low molecular weight heparins (LMWH) are safe for the fetus, but there is still debate as to their therapeutic efficacy in the mother compared with that of warfarin.29-33 UH is associated with higher rates of maternal thromboembolic complications, including fatal events.29,33 There are limited data on the efficacy of LMWH in mechanical valves during pregnancy, but valve thrombosis may occur.34 High rates of maternal valve thrombosis occur if subtherapeutic doses of UH or LMWH are used.9,30 Women should participate in the choice of anticoagulation therapy (C2). In women with other diseases (eg, dilated cardiomyopathy) who require anticoagulation therapy to prevent thromboembolic complications, the use of therapeutic or prophylactic doses of LMWH will depend on the perceived risk of thromboembolism (C1). Back to text

Objective: To estimate the risk of death from healthcare-associated (nosocomial) bacteraemia caused by methicillin-resistant Staphylococcus aureus (MRSA), and compare it with that of nosocomial bacteraemia caused by methicillin-sensitive S. aureus (MSSA), by meta-analysis of selected studies. Data sources: Medline, EMBASE, Current Contents and Cochrane Library were searched for the period January 1978 (or earliest date of the database, if later than 1978) to December 2000. Study selection: Studies which compared mortality of nosocomial MRSA and MSSA bateraemia. Data synthesis: Nine studies were analysed. All but one found an increased relative risk (RR) of death from MRSA bacteraemia, with RR ranging from 0.89 to 4.94. Meta-analysis showed that patients with MRSA bacteraemia have an RR of death, compared with patients with MSSA bacteraemia, of 2.21 (95% CI, 1.76–2.57) using the fixed-effect method, and 2.03 (95% CI, 1.55–2.65) using the random-effect method. Conclusion: MRSA bacteraemia is associated with a real increase in risk of death, further justifying ongoing MRSA surveillance and control in healthcare facilities.

Michael Whitby · Mary-Louise McLaws · Geoffrey Berry