Women's health

An adolescent with autism and intellectual disability presented with severe depression related to menstruation. Because of the complex medical, psychiatric and ethical issues involved, her care was coordinated by a hospital-based adolescent medicine unit. After trials of other therapies over an extended period and interdisciplinary and intersectoral case conferencing, it was decided that hysterectomy was the most appropriate management. This case highlights the complexity of adolescent health care in a tertiary hospital, the importance of intersectoral cooperation between hospital and community, and the integral role of interdisciplinary care of adolescent patients with chronic conditions.

S Rachel Skinner PhD, FRACP · Cindy Ng MB BS(Hons), DCH · Ann McDonald MPaed, FRANZCP · Tamara Walters FRANZCOG

The scientific benefit is clear, but translating this into practice requires advocacy Fourteen years ago, randomised controlled studies in the United Kingdom1 confirmed observational studies from Australia,2 the United States,3 and elsewhere, showing that an adequate intake of folic acid by women at around conception prevents most neural tube defects in their babies.4 These three countries now (i) have government-sponsored public health campaigns which encourage women of childbearing age to increase their daily intake of folic acid; (ii) have food standards permitting the food industry to voluntarily add folic acid to cereal and other foods; and (iii) have health benefit claims related to the prevention of birth defects. In 1996, the US (along with Canada) introduced mandatory fortification of virtually all wheat flour products. Despite recommendations by the National Health and Medical Research Council in Australia and other scientific bodies and scientists in the UK, mandatory fortification has yet to be introduced in these countries. Why should this be? After mandatory wheat flour fortification in the US, median serum folate levels in non-pregnant women of reproductive age more than doubled.3 Mandatory fortification has resulted in a 30% reduction of neural tube defects, or 1000 fewer cases every year.2 Each case of spina bifida prevented saves an estimated US$500 000 in lifetime costs.5 Even so, more could be achieved in the US compared with other countries where mandatory fortification requires higher amounts of folic acid to be added to flour than in the US.6 Examples include Canada7 (50% reduction in neural tube defects) and Chile8 (70% reduction). It is well past the time that the Australian and the UK governments should have drafted food standards with sufficient folic acid to provide 400 μg of synthetic folic acid a day to women of child-bearing age. In Australia, while the number of preventable cases (about 500 a year) has been reduced by voluntary fortification,2 this has not occurred across all of society, with resulting inequities.9,10 The reduction of cases of lifelong disability from neural tube defects has largely resulted from antenatal detection, with pregnancies being terminated (now the leading cause for late-stage termination of pregnancy in Australia and the UK). Preventing 500 neural tube defect cases each year in Australia would relieve the huge time commitment, financial cost and emotional burden from not only the affected individual, but his or her network of family, friends, work colleagues and other associates and caregivers. In the 10 years since we have known how to prevent neural tube defects, this would have meant 50 000 highly affected people in Australia alone. Folic acid fortification of flour is cheap — less than 0.1% the cost of flour (ie, less than 20 cents Australian per ton of flour). As thiamine is already a required additive, the costs of preparation and of administering quality control of the process, as well as of changing the labels on some foods, are small. Some millers and grocery companies in Australia do not favour mandatory flour fortification because they fear loss of market share for already fortified foods. However, a number of the largest milling companies, including Allied Mills and the Manildra Group, have publicly stated their support for mandatory flour fortification. The mandatory fortification of flour in the US not only prevents neural tube defects, but has also brought a wider benefit to the population, especially to older people beset with chronic and degenerative diseases. The exact degree of this benefit is still being defined, but current evidence indicates the increase in serum folate concentrations in the population is sufficient to prevent almost all folate deficiency anaemia.7 The association between lower risks for heart attack and stroke with lower homocysteine concentrations has been established.7 Since mandatory flour fortification with folic acid in the US, there have been about 17 000 fewer heart attacks and 31 000 fewer strokes.7 In addition, several recent scientific articles have credited folic acid supplementation with protection against loss of cognitive function in the elderly and Alzheimer’s disease,11 and against several cancers (including neuroblastomas). The benefits described above are clear and significant, but what are the perceived risks? One is the possibility of masking pernicious anaemia (the result of vitamin B12 deficiency) in the elderly and evolution of its neurological manifestations. Mild forms of dietary vitamin B12 deficiency in the elderly do occur, but there is no relationship between folate and vitamin B12 deficiencies. A second perceived risk is an increased risk of certain cancers, such as colon and breast cancer; however, there is mounting evidence that the overall risk of cancer is reduced, as the genome is less stable and at higher risk of mutagenesis when people are deficient in certain micronutrients, including folic acid.12 Since the US first demonstrated the benefits of flour fortification, more than 40 countries around the world have made it mandatory.13 Recently, leaders from over 50 key organisations formed The Flour Fortification Initiative, a United Nations-registered public, private, and civic alliance in support of the UN Millennium goals. With Australians in the forefront of this global movement, it is time that Australians at home also gain the benefit of this substantial public health measure. If there were a toxin (such as lead and mercury) or an infectious agent (such as the mad cow product) in the nation’s food supply, action would be swift and decisive. The ethical issue here is not what harm the mandatory fortification of flour with folic acid would do; rather, it is the harm inflicted each day that fortification is delayed by those who know how to prevent the damage from folic acid deficiency. In 2005, The National Institute of Clinical Studies Evidence-Practice Gaps Report14 identified mandatory folate fortification of flour as a key issue, and the Australian, New Zealand and UK governments will decide for or against this measure during the next 6 months. If the medical community will not rally and become advocates for this public health issue, who will? And at whose expense?

Glen F Maberly BSc(Med), MD, FRACP · Fiona J Stanley AC, FAFPHM, FRACP, FRANZCOG

Strict control of blood glucose levels should be pursued before conception and maintained throughout the pregnancy (glycohaemoglobin [HbA1c] level as close as possible to the reference range). Before conception: high-dose (5 mg daily) folate supplementation should be commenced; oral hypoglycaemic agents should be ceased; and diabetes complications screening should take place. Management should be by a multidisciplinary team experienced in the management of diabetes in pregnancy. Blood glucose monitoring is mandatory during pregnancy, and targets are: fasting 4.0–5.5 mmol/L; postprandial < 8.0 mmol/L at 1 hour; < 7 mmol/L at 2 hours. A first trimester nuchal translucency (possibly with first trimester biochemical screening with pregnancy-associated plasma protein A and β-human chorionic gonadotropin) should be offered. Ultrasound should be performed for fetal morphology at 18–20 weeks, if required, for cardiac views at 24 weeks and for fetal growth at 28–30 and 34–36 weeks. Induction of labour or operative delivery should be based on obstetric and/or fetal indications. Level 3 neonatal nursing facilities may be required and should be anticipated when birth occurs before 36 weeks, or if there has been poor glycaemic control. Insulin requirements fall rapidly during labour and in the puerperium. At this time, close monitoring and adjustment of insulin therapy is necessary.

Aidan McElduff MB BS, PhD, FRACP · N Wah Cheung MB BS, FRACP, PhD · H David McIntyre MB BS, FRACP · Janet A Lagström BSc, RM, GradCertDiabetesEd · Barry N J Walters FRACP, FRANZCOG · Jeremy J N Oats MB BS, DM, FRANZCOG · Peter Wein MB BS, FRANZCOG · Glynis P Ross MB BS(Hons), FRACP · David Simmons MD, FRACP

Medical termination of pregnancy with mifepristone, a progesterone antagonist, is available to women in North America, the United Kingdom, much of Western Europe, Russia, China, Israel, New Zealand, Turkey and Tunisia, but not Australia. Experience of mifepristone use in around two million abortions has shown that it is safe, effective, cheap to produce, and highly acceptable to women. Mifepristone is usually used in combination with a prostaglandin analogue, such as misoprostol; these drugs have been added to the World Health Organization’s list of essential medicines for developing countries. Availability of this drug in Australia might largely overcome many of the inequities of access to abortion, and is critical for many women in rural areas and women in some ethnic groups whose access to surgical abortion is limited.

Caroline M De Costa FRANZCOG, FRCOG

Results of a recent Australian trial suggest it is time to stop equivocating about screening and treatment The 1998 consensus guidelines on the management of gestational diabetes mellitus from the Australasian Diabetes in Pregnancy Society emphasised that, “due to a lack of good quality randomised controlled clinical trials in the area of [gestational diabetes mellitus], these guidelines are based on what is a reasonable consensus of informed opinion in Australasia”.1 The clear benefits of treating women with gestational diabetes according to these guidelines have now been demonstrated by the Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS).2 This study randomised 1000 women with gestational diabetes to either routine antenatal care or to an intervention that comprised home glucose monitoring, review by a diabetes educator, dietitian and physician, and insulin therapy if glycaemic targets were not met. Serious adverse perinatal outcomes occurred in 1% of the intervention group versus 4% of the routine-care group (adjusted relative risk, 0.33 [95% CI, 0.14–0.75]). The percentage of infants who were large for gestational age was lower in the intervention group (13% v 22%), with no increase in those who were small for gestational age. Although induction of labour was more common in the intervention group (39% v 29%), rates of caesarean delivery were similar (around 31%). Measures of maternal quality of life were more favourable in the intervention group. To prevent one serious perinatal outcome, 34 women needed to be treated. The 1998 guidelines were equivocal in regard to screening for gestational diabetes, allowing either for universal screening or for selective screening based on clinical risk factors in relatively low-risk populations. In the light of the findings of ACHOIS, we believe that universal screening should now be accepted and implemented. There are multiple arguments in favour of this approach: Most women with gestational diabetes have no symptoms, and many have none of the classic risk factors associated with gestational diabetes.3 Screening based on risk factors adds an extra complexity to busy routine clinical practice and may lead to some women failing to undergo appropriate testing. Furthermore, ACHOIS patients were relatively “low risk”, being predominantly of European background, with a mean age of around 30 years, and a mean body mass index of around 26 kg/m2. Many would not have been tested based on risk factors. Nonetheless, the benefits of treatment were impressive. The precise level of hyperglycaemia that carries increased pregnancy risk remains to be defined. ACHOIS used as its inclusion criterion a 2-hour venous plasma glucose level on oral glucose tolerance testing ≥ 7.8 mmol/L but < 11.0 mmol/L. The women included in the study had a median fasting glucose level of 4.8 mmol/L and a median 2-hour glucose level of 8.6 mmol/L. The current Australian criteria suggest fasting and 2-hour cut-offs of ≥ 5.5 mmol/L and/or ≥ 8.0 mmol/L, respectively, for the diagnosis of gestational diabetes.4 To avoid the confusion which could occur if multiple sets of criteria were promulgated, we suggest that the diagnostic thresholds for gestational diabetes should not be revised until the blinded prospective international epidemiological study HAPO (Hyperglycemia and Adverse Pregnancy Outcome) reports its results, which are expected by mid-2007.5 Screening for gestational diabetes also offers benefits from a public health viewpoint, at a time of increasing prevalence of obesity and type 2 diabetes.6 Screening allows identification of women with undiagnosed type 2 diabetes and those at increased risk of developing this condition in the future. Detection of gestational diabetes has the potential to benefit not only the women involved, but also their children, through intervention.7 Preventing progression from gestational diabetes to type 2 diabetes is already considered cost-effective.8 Introduction of routine screening for gestational diabetes clearly carries cost and resource implications. The number of women diagnosed with gestational diabetes will increase, and appropriate provision must be made for their care. In ACHOIS, the intervention group received care from a multidisciplinary team, which generally comprised a dietitian, diabetes educator and physician, in addition to the obstetrician and midwives. This level of care is congruent with the 1998 Australasian guidelines, but may be difficult to implement on a large scale across Australia. Other models of care may be required, with increasing involvement of midwives, general practitioners and other health care providers. There is some evidence to support the efficacy of such treatment protocols.9 However, the ACHOIS data2 suggest that something more than “routine antenatal care” is required for optimal outcomes in this patient group. Therefore, less intensive models of care should be rigorously evaluated rather than promoted ad hoc on the basis of potential cost savings. The extra costs involved in providing optimal care for women with gestational diabetes are likely to be far outweighed by savings due to reduction in adverse perinatal outcomes. Evidence and recommendations on gestational diabetes Treatment for gestational diabetes substantially reduces adverse perinatal outcomes and improves maternal quality of life. Optimal proven treatment for gestational diabetes includes review by a diabetes educator, dietitian and physician, with insulin used if glycaemic targets are not achieved. Screening for gestational diabetes should be offered to all pregnant women. Maternity service providers should ensure that adequate resources are devoted to the detection and treatment of gestational diabetes.

H David McIntyre FRACP · N Wah Cheung PhD, FRACP · Jeremy J N Oats DM, FRCOG, FRANZCOG · David Simmons MD, FRACP

To the Editor: One of the great privileges in practising obstetric medicine is to support a couple through a successful confinement when they have previously been advised against attempting pregnancy because of pre-existing maternal disease. However, in some cases, pregnancy carries a substantial risk of morbidity and mortality to both the mother and infant. Indeed, many maternal deaths in Australia are still preventable,1 and underlying cardiac disease is an important cause.2 Recently, I was consulted for preconception counselling by a young woman with dilated cardiomyopathy. Based on the limited evidence in the literature, her risk of dying as a result of pregnancy would be greater than 25%.3 Similarly, I was recently involved in the care of a young woman with Eisenmenger syndrome who elected to terminate her pregnancy due to the 50% mortality associated with pregnancy with this condition.4 Pregnancy in young women with moderate renal failure carries a significant risk of permanent decline in renal function, along with a high risk of intrauterine growth retardation and prematurity for the baby.5 Organ transplantation offers the best hope for women in this situation, as pregnancy outcomes are excellent after solid organ transplantation (with the exception of lung transplantation). However, many women have organ dysfunction severe enough to compromise pregnancy outcome, but not to warrant transplantation.6 Pregnancy in the presence of maternal disease may also pose a substantial cost to the community. A 2001 study in the United Kingdom estimated the mean cost of pregnancy care for five mothers with severe cardiac disease to be £23 000, not including the cost of neonatal care.7 One mother and one baby died. Options for couples with pre-existing maternal disease are limited. In Queensland, they are excluded from adopting a child because they are not infertile and because of the mother’s medical condition. Altruistic surrogacy would allow them to have a child that is genetically their own without risking the mother’s and infant’s health. However, legislation on surrogacy varies significantly between Australian jurisdictions (Box),8 and, in Queensland, all surrogacy arrangements — both commercial and altruistic — are illegal. Thus, my patient with dilated cardiomyopathy faces prosecution if she were to attempt surrogacy anywhere in Australia while a Queensland resident, whereas it would be freely available to her if she moved 80 km south and became a New South Wales resident. I believe altruistic surrogacy should be available for women in whom underlying medical conditions result in a significant risk of morbidity or mortality associated with pregnancy. Legislation on surrogacy arrangements in Australia* Queensland: The Surrogate Parenthood Act 1988 (Qld) makes all arrangements relating to surrogacy illegal in Queensland, imposing criminal penalties on all parties involved in both altruistic and commercial surrogacy arrangements. Tasmania: The Surrogacy Contracts Act 1993 (Tas) makes it an offence to make or receive a payment or to publish any advertisement in relation to a surrogacy contract. All surrogacy contracts are void and unenforceable. South Australia: The Family Relationships Act 1975 (SA) makes it an offence to enter into a surrogacy contract for valuable consideration, and contracts are illegal and void. Australian Capital Territory: The Parentage Act 2004 (ACT) does not prohibit non-commercial surrogacy, provided no advertising or intermediaries are involved, and payments to cover expenses are allowed. Victoria: The Infertility Treatment Act 1995 (Vic) prohibits commercial surrogacy, and has complex criteria regarding eligibility of surrogate mothers. * New South Wales, Western Australia and the Northern Territory do not have surrogacy legislation.

Adam P Morton

Comment: Morton feels that women for whom pregnancy poses a substantial risk should be offered altruistic surrogacy, so that they can still have a child that is genetically their own. The suggestion is commendable but opens a hornets’ nest. First, “genetic ownership” is a bit of a fiction at best, given that the only item genetically owned by the mother is an egg with 23 chromosomes and some cytoplasm. Admittedly, Morton refers to couples rather than to women, but few are the men who have incontrovertible evidence of any genetic stake in their alleged offspring,1 and, given the rate with which partnerships change, thousands willingly care for children in whom they know they have no genetic stake at all. After implantation of the fertilised embryo, the carrier of the pregnancy owns whatever there is to be owned, irrespective of where some of the genes came from. At birth, genetic ownership changes again, and the child becomes its own “genetic owner”. So, how much “genetic ownership” of a child can there be? Second, who would qualify for altruistic surrogacy? It seems reasonable that women with Eisenmenger syndrome should not embark on a pregnancy given the high mortality associated with it. But how do we know that collecting ova and all it entails, and the subsequent years caring for a baby/toddler/child/teenager, would not be an even greater challenge to the woman’s health than pregnancy? Third, where will these surrogates come from (especially for women without sisters or other suitable family volunteers), and how do we ensure that they will be happy to hand back the child to its “genetic owners”? How will we protect these altruistic women in subsequent years against potential law suits for alleged failures in duty of care to the child that they carried (for example, by exposure to toxins during the pregnancy)? Fourth, is there not a far easier and more logical solution to this problem, provided that egg collection does not endanger the woman’s health? Why not preserve the woman and her partner’s frozen embryos until the woman’s medical condition is sufficiently stable to both sustain a pregnancy and care for the child that hopefully results from it? If the woman’s health cannot be restored sufficiently to achieve this, these couples could then show some altruism of their own by donating the embryos to infertile couples who desperately want a child irrespective of whether they can claim “genetic ownership”. Thus far, there is little evidence that altruistic donation and genetic ownership are even half way to meeting each other.2 However, Morton should be commended for drawing attention to a national problem in women’s health. The disparities and discrepancies between the Australian states and territories in almost anything that relates to reproduction2-5 is an utter disgrace. Reproductive health should be equitable among all Australians.

Marc J N C Keirse

Christopher M MacIsaac,* Mark A Page,† Beverley-Ann Biggs,‡ Kumar Visvanathan§ * Associate Intensivist, † Registrar, ‡ Associate Professor, The Royal Melbourne Hospital, Grattan Street, Melbourne, VIC 3050; § Senior Research Fellow, Murdoch Children’s Research Institute, Melbourne, VIC. Christopher.macisaacATmh.org.au To the Editor: We report a recent case of toxic shock syndrome associated with menstruation which illustrates that this syndrome still occurs, even when tampons are used appropriately. A potential diagnostic test for the syndrome is also discussed. An 18-year-old woman presented with a 1-day history of fever, chills and severe back pain, with no other focal symptoms. On examination, she was febrile with a blood pressure of 75/40 mmHg, and had begun vomiting. She was treated empirically with intravenous ceftriaxone and flucloxacillin and resuscitated with intravenous fluids. Over several hours, the back pain resolved, and a widespread erythrodermic rash developed, centred mainly on the trunk. Further questioning revealed that the patient had removed a tampon shortly before presentation, as she had just ceased menstruating. Renal ultrasound examination, chest x-ray and blood cultures were non-diagnostic. She was treated with intravenous antibiotics for 4 days and discharged home with a further 10-day course of oral amoxycillin and clavulanic acid. At outpatient follow-up 3 weeks after admission, she reported desquamation of the skin of her palms and soles. Toxic shock syndrome was first described in 1978,1 and a strong association with Staphylococcus aureus, menstruation and tampon use was established in 1980.2 Toxic shock syndrome toxin-1 (TSST-1), a protein secreted by S. aureus, was the first of many toxins associated with the syndrome to be identified. The term “superantigen” was adopted to describe the ability of these toxins to cause a remarkable expansion of T lymphocytes displaying specific β chain variable regions of the T-cell antigen receptor. Superantigens bypass normal antigen presentation and can stimulate over 20% of all T cells, whereas a conventional antigen stimulates only in the order of 1 in 10 000 T cells. The signature feature of superantigen activity is the expansion of lymphocyte populations bearing the particular Vβ chains that bind the superantigen. In the case of TSST-1, this is Vβ2.3 Our patient consented to blood being sampled to investigate the Vβ profile of her T cells at follow-up. This investigation was part of a broader study on superantigens in sepsis that was approved by the Ethics Committee of the Royal Melbourne Hospital. The blood was stained with monoclonal antibodies against 24 Vβ families4 and analysed by flow cytometry. This showed a massive expansion of Vβ2 cells, which accounted for 28% of all CD4 lymphocytes (Box). Currently, there is no diagnostic test for toxic shock syndrome. Toxin production from cultured organisms can be established in vitro by some laboratories, but does not confirm toxin production in vivo. Detection of a “skewed” Vβ repertoire is a potential diagnostic test. Clearly, the sensitivity and specificity of the assay would need to be established before general application. To date, we have found skewed Vβ T-cell profiles in six independent cases of toxic shock syndrome. This patient had used tampons appropriately, including replacing tampons at least every 4 hours and not using them overnight, but nevertheless developed a life-threatening disease. The incidence of toxic shock syndrome peaked in the United States in 1980 and has since fallen substantially, as a result of factors including changed tampon absorbency. However, the incidence may be now increasing.5 Our case serves to remind us all to be vigilant for toxic shock syndrome in association with menstruation, and to consider the diagnosis in all patients with severe sepsis. Vβ profile of the T-cell antigen receptor of CD4 lymphocytes in a patient with toxic shock syndrome Vβ profile of CD4 cells from a patient 21 days after onset of toxic shock syndrome compared with the mean profile from 11 adult intensive-care patients with no evidence of infection. Note the massive expansion of cells carrying Vβ 2, for which toxic shock syndrome toxin-1 has known affinity.

Christopher M MacIsaac · Mark A Page · Beverley-Ann Biggs · Kumar Visvanathan

Patrick M Schlievert Professor, Microbiology, University of Minnesota, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA. patsATlenti.med.umn.edu Comment: As noted by MacIsaac et al above, my colleagues and I recently reported an increase in the incidence of staphylococcal toxic shock syndrome (TSS) in Minneapolis–St Paul in the United States, from 0.8 per 100 000 (in January 2000) to 3.4 per 100 000 (in December 2003).1 We noted that physicians across the United States were reporting TSS cases in increasing frequency. There are two major categories of staphylococcal TSS, menstrual and non-menstrual.2,3 Menstrual TSS is defined as occurring during menstruation or within the 2 days preceding its onset or the 2 days following its cessation; the illness is primarily, but not exclusively, associated with tampon use. Menstrual TSS is nearly always caused by the superantigen exotoxin, TSS toxin-1 (TSST-1).4 Superantigens significantly overactivate the human immune system to release cytokines that cause the clinical features of TSS (interleukin-1β [endogenous pyrogen]; tumor necrosis factor-α and β [capillary leak]; and interferon-γ and interleukin-2 [rash]).5 Non-menstrual TSS may occur in anyone, young or old, male or female, and today commonly follows superinfection of the upper respiratory tract after viral infection. Non-menstrual TSS is caused by TSST-1 (50%) or by staphylococcal enterotoxin B or C (together nearly 50%). The important question is what accounts for the fourfold rise in TSS that was reported in our 2004 study? We proposed several hypotheses. First, the increase in incidence partly results from the emergence of three strains of methicillin-resistant Staphylococcus aureus (MRSA), at least two of which are emerging worldwide. These strains are termed (by Centers for Disease Control [CDC] nomenclature) USA 1100 (TSST-1 positive), USA 400 (SEB/SEC, Panton–Valentine leukocidin [PVL] positive), and USA 300 (positive for an unknown superantigen as well as PVL). In our studies, USA 1100 strains currently comprise 20% of submitted isolates, compared with none before the year 2000. These isolates may produce 10 to 100 times more TSST-1 in vitro than their methicillin-sensitive S. aureus counterparts matched by pulsed-field gel electrophoresis profile. Thus, these organisms rapidly produce high levels of TSST-1, leading to TSS even when lower-absorbency tampons are used. In addition, the USA 400 and USA 300 strains are also emerging and are associated with increases in non-menstrual TSS. These latter isolates also produce more superantigens than their methicillin-susceptible counterparts. Secondly, in our 2004 study, physicians who submitted cultures to our laboratory defined cases of TSS based on patient presentation and the presence of an S. aureus strain producing one of the three causative exotoxins. Our TSS definition is likely to be broader than the strict CDC definition. Finally, we also noted that it is possible that women are beginning to menstruate and to use tampons at earlier ages. In addition, teenagers are bombarded with media advice that TSS is no longer a problem; failure to recognise the illness may lead to it becoming more severe before presentation. These lifestyle and awareness changes, combined with the emergence of high-toxin-producing strains and the expanded definition of TSS, may account for the observed increase in TSS. The increase does not appear to be caused by changes in tampon composition or absorbency.

Patrick M Schlievert

Huy A Tran Director and Associate Professor, Department of Clinical Chemistry, University of Newcastle, John Hunter Hospital, Locked Bag No. 1, Hunter Region Mail Centre, New Lambton Heights, NSW 2310. huy.tranAThnehealth.nsw.gov.au To the Editor: The interesting article by Gordon et al1 warrants further discussion with regard to the hypophosphataemia, “inappropriately” high level of serum 25‑hydroxyvitamin D, biochemical diagnosis of pancreatitis and management of hypercalcaemia. Fibroblast growth factor-23 (FGF-23) is a recently described 254‑amino-acid peptide that has been shown to have significant phosphaturic effect. It probably plays a major role in phosphate metabolism and homeostasis by rising after an oral phosphate load and falling after dietary phosphate restriction. In the patient discussed by Gordon et al, elevated FGF-23 level may, hypothetically, have been a major contributing factor to the low serum phosphate level. Although the understanding of this factor is still in its infancy, measuring the serum level of FGF-23 in the patient might have shed more light on the role of FGF-23 in phosphate homeostasis. However, FGF-23 levels do not correlate directly with serum phosphate levels, suggesting that FGF-23 exercises control via renal tubular cells, regulation of calcitriol levels or intestinal phosphate absorption. FGF-23 levels are also markedly elevated in chronic renal failure, partly in response to the chronic hyperphosphataemia and partly because of reduced renal clearance.2 Its action is independent of the traditional and better understood regulators of phosphate level, including parathyroid hormone and parathyroid hormone-related protein. The triad of high vitamin D level, hypercalcaemia and hypophosphataemia points strongly to a diagnosis of vitamin D intoxication, despite a patient history to the contrary. An alternative explanation is an inaccurate vitamin D assay from the supporting laboratory. This issue, which has been highlighted recently, has therapeutic relevance in monitoring vitamin D replacement therapy.3 In supporting the diagnosis of pancreatitis, serum lipase level remains the best biochemical test and is more specific than amylase level.4 The practice of dual amylase and lipase ordering in the investigation of such conditions is excessive, confusing and costly to the community and should be discouraged. The indication for bisphosphonate treatment in milk-alkali syndrome remains unclear and contradicts the underlying pathogenesis, which is believed to be that of excessive calcium ingestion. In the patient in question, excessive calcium ingestion overwhelmed the calcium homeostatic mechanism, resulting in severe hypercalcaemia. In such a milieu, osteoclasts would be heavily suppressed and inhibited, and thus the use of a bisphosphonate, whose major action is also by osteoclastic suppression, would be of little value other than in precipitating hypocalcaemia.5 Thus, expectant management as outlined by the authors would be sufficient to achieve normocalcaemia. As bisphosphonates are not without adverse effects,6 they should only be used after a clear diagnosis of hypercalcaemia has been made.

Huy A Tran

Adam P Morton Physician, Mater Hospital, Raymond Terrace, Brisbane, QLD 4101. AmortonATmater.org.au To the Editor: I read with interest the Lessons from Practice article on milk-alkali syndrome during pregnancy.1 I would like to offer the following comments. The patient’s alkalosis was in fact more impressive than presented, as the authors used the reference range for serum bicarbonate in non-pregnant patients. During pregnancy, serum bicarbonate levels typically fall by about 4 mmol/L to compensate for the respiratory alkalosis caused by elevated progesterone levels stimulating respiratory drive. Given the patient’s life-threatening calcium level on presentation, I am interested to know whether calcitonin treatment or even dialysis was considered while waiting for the pamidronate to take effect. An important aspect that the authors did not discuss in relation to this case is the reassuring data on the safety of both proton-pump inhibitors and H2-receptor antagonists in pregnancy. While there is more experience with the latter, two recent studies found no evidence of teratogenicity in almost 900 cases of exposure to proton-pump inhibitors in the first trimester.2,3 Clinicians should feel comfortable about prescribing these medications in pregnancy. After reporting a similar case,4 I wrote to Walco, the manufacturers of Quick-Eze, who subsequently changed their product labelling to include a warning about the number of tablets that could be safely taken each day. Disappointingly, they did not include a warning about ingestion during pregnancy, as I suggested.

Adam P Morton

Michelle V Gordon,* P Shane Hamblin,† Lawrence P McMahon‡ * Registrar, † Head, Department of Endocrinology, Western Hospital, Private Bag, Gordon Street, Footscray, VIC 3011; ‡ Head, Department of Obstetric Medicine, Sunshine Hospital, St Albans, VIC. hamblin1ATbigpond.net.au In reply: Our case appears to be consistent with typical milk-alkali syndrome. While measuring fibroblast growth factor-23 (FGF-23) level might have been of hypothetical interest, it is unlikely that it would have influenced management. Vitamin D intoxication was considered once the 25-hydroxyvitamin D results became available, and we closely questioned our patient in relation to this possibility. She was insistent that she had not taken any vitamin D supplements. It is possible either that the patient did not wish to admit to taking vitamin D or that the assay was misleading, as suggested by Tran. We agree that bisphosphonate therapy should not be advocated when the diagnosis of milk-alkali syndrome is clear. In this case, however, the patient was drowsy and very ill; the full history relating to antacid ingestion was not obtained until after the bisphosphonate therapy had been given. With regard to Morton’s comments, the hypercalcaemia settled promptly, so fortunately calcitonin treatment and other measures did not need to be considered. Drug safety in pregnancy is a difficult issue, as the effects of fetal or neonatal damage may carry lifelong implications, and even relatively rare associations need to be considered with care. In addition, many pregnant women are uncomfortable about taking prescription medications during pregnancy, even though their doctors may have a more relaxed view. Currently, over-the-counter antacids are classed as category A drugs for pregnancy, whereas H2-receptor antagonists and proton-pump inhibitors are category B1 and B3, respectively. Cimetidine has been associated rarely with neonatal hepatic abnormalities,1 and it is still too early to state with confidence that proton-pump inhibitors are “safe”, despite promising initial analyses. Ironically, the potential dangers of over-the-counter calcium-containing antacids, as demonstrated in this case report and others, are not currently adequately acknowledged. We have written to the manufacturers of Rennie tablets requesting a package label warning advising consumers not to exceed six tablets a day.

Michelle V Gordon · P Shane Hamblin · Lawrence P McMahon

Clinical record A 22-year-old woman who was 12 weeks pregnant presented to a country hospital with uncontrollable nausea and vomiting. This was initially controlled with antiemetics, but over the next 4 weeks, she continued to vomit five to six times a day. She presented again at 16 weeks’ gestation when the vomiting became more frequent, and also complained of poor visual acuity and diplopia of several days duration. At the time, there was no gait disturbance, no change in mentation, nor any associated headache. At this stage she was admitted and treated with intravenous fluids including glucose. One week into her admission, her vision deteriorated and she became confused and unsteady on her feet; she was referred to the Royal Melbourne Hospital. On initial examination in Melbourne, she was normotensive (120/80 mmHg) but drowsy. There was no neck stiffness or rash. She now had a prominent gait ataxia and a corresponding mild lower-limb peripheral neuropathy with absent deep tendon reflexes. Additionally, she had bilateral horizontal nystagmus and poor visual acuity (right, 6/36; left 6/18). There was an associated mild right gaze paresis with intact visual fields on confrontation. There was no pain with eye movements. The results of fundoscopy are shown (Figure 1). Her past history was unremarkable. She did not take regular medications, and this was her first pregnancy. Ultrasonography of the fetus and placenta at 17 weeks’ gestation excluded multiple and molar pregnancy. She did not drink or smoke. Haematological and biochemical test results were largely normal, but her serum levels of creatinine (0.04 mmol/L; normal range [NR], 0.05–0.10 mmol/L) and urea (2.2 mmol/L; NR, 2.5–6.1 mmol/L) were slightly low, and her INR (international normalised ratio) was 2.0 (NR, 0.8–1.2). There were also some elevated levels in her liver function test results: γ-glutamyl transferase, 60 U/L (NR, < 50 U/L); alanine aminotransferase, 486 U/L (NR, < 55 U/L); and bilirubin, 32 U/L (NR, 0–19 U/L). Cerebrospinal fluid (CSF) examination and magnetic resonance imaging (MRI) were also undertaken to exclude intracranial causes. The CSF findings were normal, but the MRI revealed bilateral thalamic lesions (Figure 2). Given the new clinical features and her MRI result, a diagnosis of Wernicke’s encephalopathy was made. Thiamine deficiency was suspected to be secondary to hyperemesis gravidarum. Interestingly, her serum thiamine level was only marginally low at 64 nmol/L (normal range, 66–200 nmol/L). Therapy with pyridoxine, folic acid and intravenous thiamine replacement was commenced. She made a rapid clinical recovery. Visual acuity returned to normal within 3 days and her ataxia, gaze limitation and neuropathy improved. Repeat MRI imaging 7 days later showed moderate resolution of the hyperintensities. Our patient went on to successfully deliver a healthy baby girl at 37 weeks’ gestation. 1 Fundal photographs showing gross papillitis of both the right and left optic discs, respectively. A small retinal haemorrhage is shown in the left eye. 2 Magnetic resonance imaging (T1-weighted, T2-weighted axial, and diffusion-weighted image, respectively), with arrows showing bilateral symmetrical thalamic hyperintensities with restricted diffusion. Bilateral thalamic ischaemia is most often seen in thiamine deficiency. This patient’s rapid response to intravenous thiamine replacement confirms the diagnosis of Wernicke’s encephalopathy secondary to thiamine deficiency. Thiamine, or vitamin B1, plays an important role in carbohydrate metabolism through decarboxylation of alpha-keto acids. Moreover, it also functions as a co-enzyme to the apoenzyme transkelotase in the pentose monophosphate pathway for glucose.1 Low thiamine levels can be associated with poor intake or absorption, increased demand, or poor utilisation. It is well understood that thiamine requirements are increased in pregnancy, and this is thought to be the result of sequestration of the vitamin by the fetus and placenta.2 With hyperemesis gravidarum, the deficiency is further compounded by the impaired absorption related to the intractable vomiting.3 In some situations, prolonged use of intravenous glucose without thiamine can be a potent precipitant of Wernicke’s encephalopathy.4 This phenomenon is well documented,5 and in our patient, might have contributed to the evolving deficiency. Abnormal liver function test results are also seen in Wernicke’s encephalopathy, and it is possible that hepatic derangement may have also played a pathogenic role in the evolution of our patient’s disease. 6 Our case is unusual in that visual deterioration was the first symptom of an evolving thiamine deficiency. There was a delayed presentation of the classical triad of Wernicke’s encephalopathy — ataxia, mental confusion and ocular gaze problems. Moreover, in our case, MRI scanning was able to detect sensitive neurological changes, raising the suspicion of thiamine deficiency. This information was important in prompt treatment of the condition when clinical signs began to emerge. Indeed there are reports of the usefulness of MRI imaging in diagnosing cases of Wernicke’s encephalopathy.7 Our patient’s vitamin B1 level was only mildly reduced, but this may have been the result of partial correction with food intake while an inpatient at the country hospital. Unfortunately, intracellular thiamine levels could not be measured before replacement. Intracellular thiamine level is usually a more accurate marker of thiamine deficiency, measured as erythrocyte thiamine diphosphate by high pressure liquid chromatography, and is often abnormal in such cases of Wernicke’s encephalopathy, even when the serum thiamine level is normal. If left untreated, thiamine deficiency can lead to severe neurological, cardiovascular and gastrointestinal sequelae. If not treated, the result is often death. Delayed correction of low thiamine levels may lead to persistent nystagmus, ataxia and poor concentration with multiple tasks.8 For the fetus of an affected mother, slow in-utero development is possible. Ophthalmic symptoms may include subacute, progressive visual loss, with central field defects and associated poor colour vision. Papillitis can be seen in cases of nutritional optic neuropathy. In severe cases, blindness may occur as a result of complete optic atrophy.9 As thiamine deficiency has severe consequences, we believe that vitamin B1 replacement should be considered in all pregnant women with hyperemesis gravidarum. We further suggest that in such cases MRI imaging may play an important role in early diagnosis. Lessons from practice Visual deterioration may sometimes be the first presenting sign of thiamine deficiency. The visual symptoms of Wernicke’s encephalopathy are reversible with prompt administration of thiamine. Early correction of thiamine deficiency is essential in all patients with hyperemesis gravidarum. Intravenous glucose should be given together with thiamine for patients being treated for hyperemesis gravidarum. The best laboratory measure of thiamine deficiency is erythrocyte thiamine diphosphate by high pressure liquid chromatography. Magnetic resonance imaging may help in early diagnosis of patients with Wernicke’s encephalopathy where optic neuropathy is the first clinical sign.

Mervyn D Ferdinands MB BS(Hons) · Janaka Seneviratne FRACP · Owen White MD, PhD, FRACP

Objectives: To evaluate the impact of a community-based, collaborative, shared antenatal care intervention (the Mums and Babies program) for Indigenous women in Townsville.Design and participants: Prospective cohort study of women attending Townsville Aboriginal and Islander Health Service (TAIHS) for shared antenatal care with a singleton Indigenous birth between 1 January 2000 and 31 December 2003 (456 women; the MB group), compared with a historical control group of 84 women who attended TAIHS for antenatal care before the intervention between 1 January 1998 and 30 June1999, and a contemporary control group of 540 women who had a singleton birth at Townsville Hospital between 1 January 2000 and 30 June 2003, but did not attend TAIHS for antenatal care.Intervention: Integration of previously autonomous service providers delivering shared antenatal care from TAIHS.Main outcome measures: Patterns of antenatal visits, proportion of women undertaking key antenatal screening, and perinatal outcomes.Results: The number of Indigenous women who entered the MB program and gave birth at Townsville Hospital rose from 23.8% in 2000 to 61.2% in 2003. The number of antenatal care visits per pregnancy increased from three (interquartile [IQ] range, 2–6) in the historical control group to seven (IQ range, 4–10) in the MB group (P < 0.001). 88% of women in the MB group had at least one ultrasound. About 90% of all women attending for antenatal care were screened for sexually transmitted infections. In the MB group, there was a significant reduction in preterm births compared with the contemporary control group (8.7% v 14.3%, P < 0.01). There was no significant reduction in the prevalence of low birthweight births or perinatal mortality.Conclusion: A community-based collaborative approach to shared antenatal care services increased access to antenatal care and was associated with fewer preterm births among Indigenous women in Townsville. The model may be adaptable in other urban centres with multiple antenatal care providers and significant numbers of Indigenous people across Australia.

Kathryn S Panaretto MB BS, MPH · Heather M Lee HealthWorkerCert3 · Melvina R Mitchell EN · Sarah L Larkins MPH, FRACGP · Vivian Manessis FRACGP · Petra G Buettner PhD · David Watson FRANZCOG

Obstetric services need to be women-centred and based on mutual respect and collaboration Obstetricians and midwives have complementary roles in the care of pregnant women, and each group would find survival without the other difficult. Nor would women necessarily receive the best care if access to one or other of these professions were restricted. Having complementary roles, though, has not prevented hostility or “turf” wars between the two groups, with midwives claiming that maternity services are over-medicalised,1 and obstetricians counter-claiming that there is no demand for midwife-led care.2 So what is the current modus vivendi for obstetricians and midwives, and to where feasibly could it evolve by 2020? By 2020, it can only be hoped that an Australian National Maternity Policy will be in place. Maternity services in Australia in 2005 provide much choice for women, including private or public care by obstetricians, general practitioners and midwives. These services can take place in traditional hospital obstetric units, birthing centres and, now less frequently, at home. Australia has not followed the New Zealand model of care in allowing women to choose a midwife as a “lead maternity carer” as a mainstream option in the public health system. However, in some Australian states, this may soon change.3 If this were to eventuate, Australia would do well to look at the lessons learned from the experience in New Zealand. Across the Tasman many positive changes have resulted from maternity services reform, such as significant improvement for many women in continuity of maternity caregiver, and greater availability of non-medically based models of care for those women wanting them. But negative changes have also occurred, such as the effective loss of the option for women to have a GP involved in their maternity care, and an initial exodus of experienced midwives out of the public hospital system. In particular, the sheer pain of major change, for both women and care providers, could have been minimised by thorough and consultative planning. Given all this choice, why should there be hostility between obstetricians and midwives? The main criticisms from midwives stem from a perception that obstetric care in Australia is too medicalised and that obstetric intervention rates are too high.4 Because better continuity of care from a known midwife may lead to fewer obstetric interventions5 and greater certainty for women, there has been a strong push by midwives and consumer groups, such as the Maternity Coalition, for funded midwife-led care.6 On the other hand, obstetricians point to an established system of care, with low rates of maternal and perinatal morbidity as well as generally high levels of community satisfaction.2 Provision of maternity services in Australia has also been made more difficult by workforce issues. The average age of obstetricians in Australia is 51 years7 and of midwives 41 years.8 The workforce survey carried out by the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) in 2003 revealed that a quarter of Australian Fellows were now aged 60 or more.7 The same workforce survey also highlighted the possibility of a major shortage of obstetricians in the next 10 years, due to retirements, new RANZCOG Fellows not wishing to practise obstetrics, increased feminisation of the obstetric workforce, and problems associated with safe working hours.7 There has also been a major decrease in GPs practising obstetrics, especially in rural areas, for lifestyle reasons and because of the cost of medical indemnity.9 The shortage of midwives is also a problem. The Australian Health Workforce Advisory Committee estimates a current national shortage of 1850 midwives, and this is expected to increase over the remainder of the decade.8 Problems with recruiting and retaining midwives seem to be related to midwives’ perceptions of a lack of professional recognition, stress and workload issues, as well as limited opportunities for midwives to practise as primary carers and provide continuity of care to women.10 To facilitate discussion between maternity care providers, the RANZCOG re-established the Joint Committee for Maternity Services in 2002. This has representatives from the RANZCOG, the Australian College of Midwives, the Royal Australian College of General Practitioners, and the Australian College of Remote and Rural Medicine, as well as consumer representation. Each representative feeds back to his or her governing body, with the committee proving useful in airing problems and encouraging a collaborative approach to maternity care provision. The committee has made some progress in reviewing international clinical guidelines for possible use in Australia, but has been hampered by lack of funding, obstetricians suspicious of change, and midwives frustrated by lack of change. Difficulties have arisen in reconciling differences between obstetricians, GPs and midwives in how to provide safe evidence-based care that will not diminish current levels of safety. By 2020, it can only be hoped that an Australian National Maternity Policy will be in place. At present, there is none. If this is to occur, obstetricians, GPs and midwives must work to develop collaborative policies that are women-centred, not provider-centred, and which will ensure individualised care to meet the particular needs of each pregnant woman. The development of adequate continuing professional development programs (CPD) for all maternity care providers should be mandatory, and the development of some joint CPD programs crossing profession groups would be useful. There should be development of systems of care that allow for continuity of care for women during pregnancy, labour and postnatally, but which protect against burnout of care providers. There are already good examples of effective services in various places across Australia, ranging from large metropolitan units, such as the Adelaide Women’s and Children’s Hospital Community Midwifery Program, to rural services, such as those provided at Wangaratta Hospital in Victoria, that are women-centred and based on mutual respect and collaboration between obstetricians and midwives. The challenge is to make this the norm for the benefit of mothers and babies as well as their care providers.

Edward W Weaver MB BS, FRACOG · Kenneth F Clark MB ChB, FRANZCOG · Barbara A Vernon BA(Hons), PhD

Aim: To estimate national rates of induced abortion in Australia from 1985 to 2003, using Medicare claim statistics for private patients and hospital morbidity statistics for public patients.Design and setting: Estimates were based on Australian and South Australian data collections relating to abortions. SA hospital morbidity statistics were compared with SA statutory notifications of abortions to estimate the accuracy of these collections. Medicare statistics on abortion procedures performed on private patients in South Australia were then compared with hospital morbidity statistics for private patients. National statistics on abortion derived from Medicare and hospital morbidity statistics were adjusted for inaccuracies found in these sources.Main outcome measures: Numbers of induced abortions in Australia for each year from 1985 to 2003; abortion rates per 1000 women aged 15–44 years.Results: Abortion numbers based on Medicare claims by private patients overestimated by 18.7% the number of abortions derived from statutory notifications in South Australia during the period 1988–89 to 1999–00. Hospital morbidity data using principal diagnosis codes relating to medical abortion overestimated statutory notifications by 2.3% (mainly because of readmissions). National statistics were adjusted for these overestimations and for the estimated 14.1% of private patients who would not have submitted Medicare claims (based on surveys of private-clinic patients in New South Wales and Victoria). The estimated Australian abortion rate increased from 17.9 per 1000 women aged 15–44 in 1985 to a peak of 21.9/1000 in 1995, then declined to 19.7/1000 in 2003 (estimated number of abortions, 84 460).Conclusion: There are no data currently available for deriving accurate numbers of induced abortions in Australia. Suggestions are made for collection of national statistics.

Annabelle Chan MB BS, FAFPHM · Leonie C Sage RN, RM

Objectives: To determine population-based rates and outcomes of hypertensive disorders in pregnancy.Design: Cross-sectional study using linked population databases.Setting and participants: All women, and their babies, discharged from hospital following birth in New South Wales, between 1 January 2000 and 31 December 2002.Main outcome measures: Rates of hypertensive disorders in pregnancy, maternal and infant morbidity and mortality, and level of hospital care for the birth admission.Results: 250 173 women and their 255 931 infants were included in the study. Overall, 24 517 women (9.8%) had a hypertensive disorder in pregnancy, including 1411 (0.6%) with chronic hypertension, 10 379 (4.2%) with pre-eclampsia, 731 (0.3%) with chronic hypertension with superimposed pre-eclampsia, and 10 864 (4.3%) with gestational hypertension. Women with, and infants exposed to, hypertension were more likely to suffer death or major morbidity than those without hypertension. Infants of mothers with hypertension were more likely to be to born preterm and small for gestational age. Just over half the women with major morbidity or mortality delivered in hospitals with a high level of medical care. In contrast, most infants with major morbidity or mortality were delivered in hospitals with neonatal intensive care units.Conclusions: Hypertension is a common complication of pregnancy, and adverse outcomes are increased among hypertensive women and their babies. Clinicians appear to be better at identifying and seeking an appropriate level of care for pregnancies where the infant is at risk of a poor outcome than when the mother is at risk. More specific antenatal indicators of poor maternal outcome would help guide the referral of hypertensive women to higher levels of care.

Christine L Roberts MB BS, DrPH · Jane B Ford BA(Hons), PhD · David J Henderson-Smart FRACP, PhD · Charles S Algert BSc, MPH · Jonathan M Morris FRANZCOG, PhD

Clinical record A 35-year-old pregnant woman (gravida 4, para 3) presented in February 2004 at 35 weeks’ gestation with a 1-day history of vomiting, abdominal pain and drowsiness. She had no significant past medical history, was not taking any prescription medication, and had had an uncomplicated pregnancy up to that time. Her level of consciousness subsequently deteriorated, and she became responsive only to painful stimuli. She had a blood pressure of 190/110 mmHg, abdominal tenderness and generalised oedema. Urinalysis was positive for protein and leukocytes. Blood biochemical levels included creatinine 0.19 mmol/L (reference range [RR], 0.05–0.09 mmol/L); urea 9.2 mmol/L (RR, 2.5–8.3 mmol/L); ionised calcium 2.64 mmol/L (RR, 1.12–1.3 mmol/L); bicarbonate 32 mmol/L (RR, 22–28 mmol/L); amylase 2397 IU/L (RR, < 160 IU/L); lipase 1364 IU/L (RR, < 60 IU/L); urate 0.65 mmol/L (RR, 0.2–0.47 mmol/L); and phosphate 0.58 mmol/L (RR, 0.8–1.5 mmol/L). Abdominal ultrasound excluded acute cholecystitis. A fetal cardiotocograph showed reduced variability in fetal heart rate. Pre-eclampsia was diagnosed, and the woman underwent an urgent caesarean section 3 hours after presentation. The pre-eclampsia was managed with magnesium sulfate infusion, intravenous hydralazine and metoprolol. A 2574 g boy was delivered (Apgar score 3 at 1 minute, 9 at 10 minutes). Initially, he had a blood pH of 7.37 and serum calcium level of 4.12 mmol/L (RR, 2.1–2.6 mmol/L). Within 1 week he had made a full recovery from respiratory distress, jaundice and sepsis. Neonatal hypocalcaemia did not occur. Subsequently, a computed tomography (CT) scan of the woman’s abdomen confirmed acute pancreatitis, with an oedematous pancreas and fluid in the paracolic gutter (Box 1). Her serum parathyroid hormone (PTH) level on Day 2 was suppressed (0.66 pmol/L; RR, 1.3–6.8 pmol/L), with PTH-related protein undetectable (< 1 pmol/L). On Day 7, her serum 25-hydroxy-vitamin D level was inappropriately high (120 nmol/L; RR, 25–108 nmol/L). (On later questioning, she said she had not taken vitamin D supplements.) The level of 1,25-dihydroxyvitamin D was not measured. The serum level of angiotensin-converting enzyme was normal. The patient’s hypercalcaemia was managed by intravenous administration of saline, followed by frusemide and pamidronate 90 mg. Over the next few days, her condition improved and her blood pressure and renal function normalised. The hypercalcaemia resolved quickly — to the extent that, by Day 8, she had developed symptomatic hypocalcaemia requiring oral supplementation with calcium carbonate and calcitriol (Box 2). When her delirium had resolved, she reported a 1-month history of severe heartburn, for which she had self-medicated with antacids, taking up to 10 Rennie tablets a day (an over-the-counter [OTC] preparation containing calcium carbonate 680 mg and magnesium carbonate 80 mg per tablet) (10 tablets contain about 3 g elemental calcium). She had also been drinking up to three glasses of milk a day. In light of this history, milk-alkali syndrome was diagnosed, and the pancreatitis was attributed to hypercalcaemia. By Day 16, the pancreatitis had resolved and the calcium level normalised. She was discharged home without medication and has remained well. Milk-alkali syndrome — the triad of hypercalcaemia, metabolic alkalosis and renal insufficiency1 — is associated with ingesting large amounts of calcium and absorbable alkali. Before the advent of modern treatment for peptic ulcer disease (with H2-receptor antagonists, proton-pump inhibitors and antimicrobial therapy), excessive calcium intake related to over-the-counter (OTC) antacid preparations commonly caused hypercalcaemia. In recent years, there has been a resurgence of milk-alkali syndrome. In a series of 100 patients admitted with hypercalcaemia between 1990 and 1993, it was reported as the third most common cause (12%) of hospital admissions for hypercalcaemia after primary hyperparathyroidism and hypercalcaemia of malignancy.2 Reasons for this include the recent emphasis on calcium therapy for osteoporosis, ready availability of OTC calcium preparations, and the use of calcium carbonate rather than aluminium (as a phosphate binder) in patients with advanced chronic kidney disease. Oral calcium carbonate is now the predominant source of calcium and alkali associated with the development of milk-alkali syndrome (with or without milk intake). The amount of calcium carbonate required to be ingested per day to cause milk-alkali syndrome is reported to vary from as low as 4 g to as high as 60 g.3,4 Thus, there appears to be no direct link between the amount of calcium ingested and development of the syndrome, although reports are few.2 After as little as 1 week of treatment with calcium carbonate, patients can present with symptoms of hypercalcaemia, severe metabolic alkalosis and acute renal failure.5 Three previous cases of milk-alkali syndrome complicating pregnancy have been reported,6-8 one with associated pancreatitis. In our case, the pancreatitis resolved quickly as the calcium level fell. The parathyroid hormone (PTH) concentration was appropriately suppressed in response to the hypercalcaemia. The subsequent hypocalcaemia resulted from cessation of the high calcium ingestion together with suppression of PTH. This was compounded by the concurrent administration of pamidronate and, possibly, by calcium sequestration and fat saponification associated with the pancreatitis. Although we have attributed the pancreatitis to hypercalcaemia, it should be noted that the causal association between hypercalcaemia and pancreatitis is disputed. In a Mayo Clinic series of 1153 patients with hyperparathyroidism, the incidence of pancreatitis (1.5%) was similar to that in the general population.9 Pregnancy itself has also been independently associated with pancreatitis.10 The diagnosis of milk-alkali syndrome depends on a history of ingestion of excess calcium and absorbable alkali with exclusion of other causes of hypercalcaemia. Only a minority of exposed patients appear to develop the syndrome. Kapsner et al reported that, of 297 cardiac transplant patients receiving large doses of calcium carbonate as prophylaxis for osteoporosis, 65 patients developed hypercalcaemia but only three had milk-alkali syndrome.11 Susceptibility appears to depend upon variables such as pre-existing renal disease and concurrent medications (eg, thiazide diuretics and vitamin D supplements). Management of the syndrome includes removal of the precipitating (dietary) cause, together with rehydration. In pregnancy, additional complications may involve the fetus (suppression of fetal parathyroid function, neonatal hypocalcaemia and tetany). Our patient had experienced a fairly typical pregnancy, heartburn being a common symptom in pregnant women. An OTC preparation that she took to relieve the heartburn caused life-threatening biochemical derangements, and other pregnant women are potentially susceptible to such a course of events. A diagnosis of milk-alkali syndrome may be missed unless a detailed history is obtained, and information about OTC preparations is essential in all patients presenting with hypercalcaemia. As H2-receptor antagonists and proton-pump inhibitors are not often prescribed in pregnancy for gastro-oesophageal reflux symptoms, many women rely on OTC heartburn relief medication. It is therefore important to educate pregnant patients about OTC calcium carbonate-containing antacids. A limit of 1.2–1.5 g per day of elemental calcium (3.0–3.75 g calcium carbonate) appears safe.2 This equates roughly to six Rennie tablets, five Quick-Eze tablets, 150 mL Mylanta Plus suspension or 230 mL Gaviscon liquid. Interestingly, Gaviscon tablets and all other preparations (liquid or tablets) of Mylanta (except Mylanta Rolltabs) contain no calcium. Appropriate warning labels on all OTC calcium-containing preparations would help prevent further cases of this type. Lessons from practice Gastro-oesophageal reflux (“heartburn”) in pregnancy is common. Excessive use of over-the-counter (OTC) calcium-containing antacids to relieve this condition can lead to milk-alkali syndrome. Pregnant women need to be educated about the potential risks of milk-alkali syndrome. All patients presenting with hypercalcaemia should be asked about their use of OTC medications. A daily dose of six Rennie or five Quick-Eze tablets appears safe; alternatively, one of the many non-calcium containing antacids can be recommended. 1 Abdominal computed tomography scan at Day 2 The scan shows an oedematous pancreas (arrow) and fluid in the left paracolic gutter (arrowhead). 2 Serum calcium and albumin levels during the patient’s hospital stay

Michelle V Gordon MB BS(Hons) · P Shane Hamblin MB BS(Hons), FRACP · Lawrence P McMahon MD, BS, FRACP

Lourdes I St George,* Daniel Lin† * Obstetrician and Gynaecologist, Suite 4, 36 Belmore Street, Burwood, NSW 2134. † Paediatrician, Westmead Private Hospital, Westmead, NSW. lourdesstgeorgeATbigpond.com To the Editor: A 33-year-old woman, who had borne five children and had had previous caesarean sections, presented in her eighth pregnancy with worsening malabsorption after biliopancreatic diversion for morbid obesity, performed 3 years earlier. Before surgery, she had weighed about 130 kg (height,161 cm; body mass index [BMI], 46 kg/m2); she had gradually reduced her weight to 67 kg. Her surgery had created intestinal malabsorption resulting from the intestinal bypass and from dietary restriction because of gastroplasty. The physiological stress associated with pregnancy worsened her anaemia from protein and vitamin deficiencies, especially fat-soluble vitamins and calcium. She required frequent hospitalisation for intravenous fluids to compensate for dehydration from vomiting and diarrhoea. She was taking oral iron, folate, vitamin D, a calcium supplement, vitamin B12, and having vitamin K injections. Her total weight gain in pregnancy was poor (from 71 kg to 74 kg). At 32 weeks she presented with premature labour and a persistent low fetal baseline heart rate of 90 beats per minute and an unstable lie. She had an emergency caesarean section and delivered a baby boy with a birth weight of 2095 g (average for gestational age). Apgar scores were 7 and 8 at 1 and 5 minutes, respectively; the baby required ventilation for hyaline membrane disease and phototherapy for jaundice, although his blood profile was normal. His clinical course thereafter was uneventful. Obesity (BMI > 30 kg/m2), has become the epidemic of the 21st century, with one in two Australian women being overweight or obese. 1 Morbid obesity (BMI > 40kg/m2) is associated with a 6–12-fold increase in mortality.2 A multifaceted approach is essential for treatment in all patients with obesity, but unfortunately, medical treatment mostly produces short-term weight loss. Thus, bariatric surgery is being performed more frequently. Biliopancreatic diversion has two components: a limited gastrectomy results in reduction of oral intake, inducing weight loss, especially during the first postoperative year; and the construction of a long limb Roux-en-Y anastomosis with a short common “alimentary” channel of 50 cm length, which maintains weight loss long term. Scopinaro, who pioneered this technique, has published long-term results reporting 72% excess body weight loss maintained for 18 years.3 He documented 239 pregnancies in 1136 patients who had undergone biliopancreatic diversion, 25% of whom had been infertile before the operation. During pregnancy, 20% required parenteral nutrition and had fetuses that were small for gestation age. The women had a mean weight gain of 6 kg during their pregnancies, and 80 % delivered babies at term with a mean birth weight of 2.8 kg. 4 From the patient’s perspective, the great advantage of biliopancreatic diversion is the ability to eat a normal diet and still achieve excellent, long-term weight loss. The most serious potential complication is protein malnutrition, with a need to take supplemental calcium and vitamins, particularly vitamin D, lifelong. Because of this potential for significant complications, patients who have had biliopancreatic diversion require lifelong follow-up and pregnancy should be avoided. Ideally this operation should be performed in women who have completed their childbearing.

Lourdes I St George · Daniel Lin

Various claims have been made about the benefits of transdermal progesterone creams for relieving symptoms of menopause. Peer-reviewed articles have reported that the creams can raise plasma progesterone levels slightly, but have no effect on vasomotor, psychosexual or mood symptoms, bone metabolism or plasma lipid levels. Currently available progesterone creams can not be recommended for treatment of symptoms associated with menopause.

Barry G Wren MD, MHPEd, FRANZCOG

Barry N J Walters,* Sivanthi Senaratne† * Physician in Obstetric Medicine, University of Western Australia, Subiaco, WA; † Registrar in Obstetric Medicine, Sir Charles Gairdner Hospital, Perth, WA. banjowATiinet.net.au To the Editor: The “Consensus statement on diabetes control in preparation for pregnancy”1 presents a counsel of perfection that is, regrettably, a cry in the wilderness in this most imperfect of all imperfect worlds. None will deny that the glycaemic target specified would represent a wonderful achievement in a woman attending in early pregnancy. Unfortunately, we are far from achieving this goal, for a variety of reasons. Firstly, and most importantly, “preparation for pregnancy” is unusual. At our clinic (King Edward Memorial Hospital, Perth), where we see up to 90 women each year whose diabetes (types 1 and 2) antedated pregnancy, fewer than 15% have been seen for preconceptional counselling, and a similar proportion have an HbA1c level below 7%. Moreover, at the same hospital, the rate of unplanned pregnancy in the general antenatal clinic exceeds 50%. Studies elsewhere have shown that the rate of unplanned pregnancy in women with diabetes is the same or greater,2 and this figure accords with our own observations. Finally, in many women of reproductive age with diabetes, glycaemic targets as recommended by the Diabetes Control and Complications Trial Research Group3 and the recent consensus statement1 are infrequently met. One study of young adults in a type 1 diabetes clinic4 revealed that “. . . only 3.4% . . . achieved an average HbA1c of less than 7% during 11 years of study . . . despite regular specialist physician, specialist diabetes nurse and dietitian input and repeatedly following up failed appointments”. Australian findings are probably not substantially better in this group. Unfortunately, levels espoused by the above authorities are difficult to attain outside the sequestered environment of a clinical trial. Thus, the realisation of the St Vincent declaration,5 which sought to normalise obstetric outcome for women with diabetes, has proven elusive. Statements that recommend ideal levels of glycaemic control before pregnancy, while laudable, are unlikely to improve the high rates of miscarriage, congenital abnormality, preterm birth and perinatal mortality that we observe. What, then, can we do? The most important intervention in the care of fertile women with diabetes is effective contraception, with the aim of preventing pregnancy until adequate control of diabetes has been achieved. Numerous studies have shown that women who plan their pregnancy and attend for preconceptional care demonstrate better periconceptional glycaemic control and, accordingly, lower rates of adverse events in pregnancy.6 Only by raising the matter of family planning repeatedly with all our younger female patients can we hope to avoid the disappointing observation of an unplanned pregnancy, with all its adverse consequences for the woman with diabetes and her baby.

Barry N J Walters · Sivanthi Senaratne

H David McIntyre,* Jeff R Flack† * Director, Endocrinology and Obstetric Medicine, Mater Health Services, South Brisbane, QLD; † Director, Diabetes Centre, Bankstown–Lidcombe Hospital, Bankstown, NSW. David. McIntyreATmater.org.au In reply: Walters and Senaratne raise two important points — that specific preparation for pregnancy is the exception rather than the rule, and that many people with diabetes (including women of childbearing age) demonstrate poor glycaemic control. As a first step to improving this situation, we believe it is reasonable to set a goal. We sought to alert clinicians, especially those with limited experience in this area, to the importance of optimal glycaemic control in preparation for pregnancy. We hope that the consensus statement represents a “signpost” rather than a forlorn “cry in the wilderness”. Many opinions were sought in developing the consensus statement. Some, for reasons similar to those given by Walters and Senaratne, thought the “HbA1c < 7%” goal too strict, while others believed it to be far too lax. In the end, we agreed to include this figure, with the proviso that the level of glycaemia should be the best achievable for each individual patient. We must educate women of childbearing potential with diabetes and their caring health professionals about the need for preconceptional diabetes control as part of their care. In some clinical circumstances, such as assisted reproduction, the timing of conception is actually determined by the treating doctor. In this setting, optimal glycaemic control should be a prerequisite for active treatment. Rather than taking a nihilistic view, clinicians should devote their combined talents and energy to providing optimal pre-pregnancy care to those women with diabetes who do plan their pregnancies, to promoting pre-pregnancy care (including contraception) for those who currently do not, and to assuming an advocacy role in promoting access to and funding for intensive treatment programs for all people with diabetes.

H David McIntyre · Jeff R Flack

To the Editor: de Crespigny and Savulescu1 criticise legal and media attention given to the abortion of a 32-week fetus with suspected dwarfism in a case in which the expectant mother had become suicidal. At the same time, they appeal to populism to support legislative change in favour of easier access to late-term abortion. This paradox raises an intriguing point about public opinion and medical ethics. How can members of the public develop opinion unless they are told what is going on? The case was made known to the public (although the patient’s name and face were not shown) because a newspaper editor considered it to be of great interest to many people. The public rightly has an interest in this tragic case, as it relates to at least three controversial themes of significance to public and social health — disability, suicide and abortion. Unfortunately, in recent decades, balanced and informed debate about abortion has been lacking. Instead, the issue has been portrayed simplistically in terms of a woman’s “right to choose”, with little research into the desperate and often coercive circumstances and the harmful consequences of those choices. That late-term abortions are subject to unclear and complex state laws is testament to the fact that abortion is far from a closed case for the public, healthcare professionals and politicians. de Crespigny and Savulescu acknowledge that the case raises “profound and divisive ethical issues”. Yet, they later assure readers that the case “appears to be ethical”, adding to their overall implication that, if only Australia’s laws were clear, uniform and liberal, the media and the public would not have had any business in the matter. Many aspects of the doctor–patient relationship are regulated by legislation — an “intrusion” that is accepted in jurisdictions in which democracy and state-funded healthcare coexist, and necessarily so, to protect both doctor and patient. If legislative change is to occur, public consultation must be sought, and the public must be given more, not less, information about abortion.

Selena R Ewing BHSc

To the Editor: The article by de Crespigny and Savulescu is certainly thought provoking and timely. The harms they cite as caused by an uncertain legal environment are lamentable, although the outcomes were probably the result of multiple factors in addition to the justice system. To bring order, reason, compassion and justice to a clinical problem as complex as termination of pregnancy — especially late termination — requires a framework for decision-making. This should operate at the hospital level, at the national level among the professionals involved, and, as de Crespigny and Savulescu contend, in the national legal system. Most hospitals have now developed consistent guidelines to assist clinicians and patients in decisions regarding pregnancy termination (in the past, there was significant intrahospital diversity and uncertainty). More recently, clinicians involved with late termination of pregnancy for fetal abnormality in eight centres in six states and the Australian Capital Territory met in Melbourne to develop a consistent national set of guidelines. There was adequate consensus to produce a document that will soon be submitted for publication for wider community comment. Hopefully, this will facilitate better outcomes for all and perhaps even provide a stimulus for review and consistency of abortion laws.

Leslie Reti SM, FRCOG, FRANZCOG

In reply: Reti is correct that the outcomes of the late abortion case probably resulted from multiple factors in addition to the justice system. A pivotal one was the decision to divulge confidential patient information before there had been a thorough internal review. It is pleasing that hospitals are developing consistent guidelines, although, as we indicated in our article, these guidelines should not include responsibility for clinical decision-making by committee. The responsibility for clinical decision-making should reside with the doctor, and committees should have a purely advisory role. Consistent national professional guidelines are needed. These could be a stimulus for law reform. Without reform, it is only a matter of time before a single complaint about a case leads to a similar succession of adverse outcomes. Ewing writes that we “criticise legal and media attention given to the abortion”. We have no criticism of the media attention and would not presume to criticise the legal processes. Our criticism was of the “decision to expose the events to legal and media scrutiny”. That is, we criticised the decision to expose the case and those involved before a thorough internal review had been conducted. We support transparency and believe that secrecy in relation to medical procedures is contrary to public interest. We agree with Ewing that public consultation must be sought before legislative change. But one thing is clear — abortion law reform is essential. It is unacceptable that, in some cases, such as the late-abortion case we described, doctors may be charged with an indictable offence whether they agree to perform the abortion or not — under the law on abortion or child destruction if they agree to abortion, or under the law of homicide by negligence if they refuse abortion and the patient subsequently commits suicide.

Lachlan J de Crespigny MD, FRANZCOG · Julian Savulescu MB BS, BMedSci