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JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY

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CME ARTICLE

Screening for Group B Streptococcus in Pregnancy


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OBSTETRICS

Renal Disease in Pregnancy Carbetocin in the Prevention of Postpartum Haemorrhage


GYnaecologY

Prevention & Treatment of Osteoporosis in Women


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JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY

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Journal Watch

177 Dry vaginal swabs feasible alternative for self-screening for HPV  Vaginal vitamin C effective prophylactic against recurrent bacterial vaginosis 178 Low risk of mental disorders in children born by assisted reproduction  Incidence density and aetiology of acute febrile illnesses among children in Asia

178

179  Hypertrophic cardiomyopathy in infants with congenital hyperinsulinism  Eating behaviours among young children positively associated with serum non-HDL cholesterol 180  Small tablets, syrup preferred oral formulations among preschool children

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Editorial Board
Board Director, Paediatrics Professor Pik-To Cheung Associate Professor Department of Paediatrics and Adolescent Medicine The University of Hong Kong Board Director, Obstetrics and Gynaecology Professor Pak-Chung Ho Head, Department of Obstetrics and Gynaecology The University of Hong Kong

Professor Biran Affandi University of Indonesia Dr Karen Kar-Loen Chan The University of Hong Kong Professor Oh Moh Chay KK Womens and Childrens Hospital, Singapore Associate Professor Anette Jacobsen KK Womens and Childrens Hospital, Singapore Professor Rahman Jamal Universiti Kebangsaan Malaysia Dato Dr Ravindran Jegasothy Hospital Kuala Lumpur, Malaysia Associate Professor Kenneth Kwek KK Womens and Childrens Hospital, Singapore Dr Siu-Keung Lam Prestige Medical Centre, Hong Kong Professor Terence Lao Chinese University of Hong Kong Dr Kwok-Yin Leung The University of Hong Kong

Dr Tak-Yeung Leung Chinese University of Hong Kong Professor Tzou-Yien Lin Chang Gung University, Taiwan Professor Somsak Lolekha Ramathibodi Hospital, Thailand Professor Lucy Chai-See Lum University of Malaya, Malaysia Professor SC Ng National University of Singapore Professor Hextan Yuen-Sheung Ngan The University of Hong Kong Professor Carmencita D Padilla University of the Philippines Manila Professor Seng-Hock Quak National University of Singapore Dr Tatang Kustiman Samsi University of Tarumanagara, Indonesia Professor Alex Sia KK Womens and Childrens Hospital, Singapore

Dr Raman Subramaniam Fetal Medicine and Gynaecology Centre, Malaysia Professor Walfrido W Sumpaico MCU-FDT Medical Foundation, Philippines Professor Cheng Lim Tan KK Womens and Childrens Hospital, Singapore Professor Kok Hian Tan KK Womens and Childrens Hospital, Singapore Professor Surasak Taneepanichskul Chulalongkorn University, Thailand Professor Eng-Hseon Tay Thomson Women Cancer Centre, Singapore Professor PC Wong National University of Singapore Adjunct Professor George SH Yeo KK Womens and Childrens Hospital, Singapore Professor Hui-Kim Yap National University of Singapore Professor Tsu-Fuh Yeh China Medical University, Taiwan

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Review Article Gynaecology

181 Prevention and Treatment of Osteoporosis in Women: An Update Osteoporosis is a growing health problem in the ageing population. A postmenopausal woman has an
approximately 50% lifetime risk of suffering an osteoporotic fracture with hip fractures carrying the highest morbidity and mortality. Non-pharmacological prevention strategies focus on attainment and maintenance of a high peak bone mass. Pharmacological interventions include hormone replacement therapy in women with early menopause and postmenopausal women until the age of 60 in the absence of contraindications. Anna Daroszewska

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Review Article Obstetrics

195 Renal Disease in Pregnancy Pregnancy in women with chronic kidney disease is associated with risks of accelerated decline in
renal function in the mother and adverse outcomes for the infant, including prematurity and growth restriction. Managing these risks requires collaboration between patient, nephrologist, neonatologist, and obstetrician. This review discusses the approaches to managing pregnancy in women with chronic kidney disease. Matt Hall, Nigel J Brunskill

In Practice

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206 Dermatology Clinic: Sudden Onset of Blistering Lesions in a Young Boy


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JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY

SEP/ O CT Vol. 39

2013 No. 5

Review Article Obstetrics

207 Carbetocin in the Prevention of Postpartum Haemorrhage: An Asian Perspective Postpartum haemorrhage (PPH) is one of the leading causes of maternal morbidity and mortality. While the
rate of PPH varies widely among different countries, it accounts for approximately 30% of maternal deaths in Asia. Carbetocin, an oxytocin agonist with pharmacological properties similar to natural oxytocin, is a promising alternative uterotonic agent for the prevention of PPH. Shilla Mariah Yussof, Horng Yen Wee

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211 In Practice (Answers)


Continuing Medical Education
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213 Screening for Group B Streptococcus in Pregnancy Group B Streptococcus (GBS) is the most frequent cause of severe early-onset neonatal infection, which is
associated with a high rate of morbidity and mortality. Because the early-onset disease develops shortly and rapidly after birth, there has been little improvement in the disease treatment, and the focus thus lies in disease prevention. This review article discusses the current screening methods for GBS in pregnancy, the guidelines by the Centers for Disease Control and Prevention, the improvement in laboratory techniques, and a pilot study in Hong Kong. KY Leung, Teresa WL Ma, KKW To, KY Wong, Thomas Li, CW Law, Sarah Morag McGhee

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Journal Watch

merase chain reaction. Questionnaires were also

bacteria such as Gardnerella vaginalis, Prevotella spp, Mobiluncus spp, Mycoplasma hominis , and Atopobium vaginae. The disorder can become chronic, but a recent study has shown that the application of vaginal ascorbic acid (vitamin C) tablets has a prophylactic effect. The randomized, multicentre, double-blind trial assessed the efficacy of vaginal vitamin C versus placebo in 142 women (age, 1850) who had a history of recurrent bacterial vaginosis. The women were randomly assigned to receive vitamin C 250 mg/day (n = 74) or placebo (n = 68) for 6 consecutive days after menses once a month for 6 months. Patients were discontinued from the study once a relapse occurred. The intention-to-treat population included all women who met the study inclusion criteria and who received at least one dose of medication. No significant differences in recurrence rate were observed among vitamin C and placebo recipients in the intention-to-treat population at 3 months (6.8% vs 14.7%), but after 6 months of treatment significantly fewer women in the vitamin

GYNAECOLOGY

administered to determine preferences and test acceptability. Thereafter, standard colposcopy examinations were performed, during which a physi-

Dry vaginal swabs feasible alternative for self-screening for HPV

cian obtained a cervical sample using a broom-like device. The samples were stored in liquid cytology medium and were subsequently used to prepare cytology slides; the residual liquid was tested for HPV using a Hybrid Capture HPV DNA test (HC). Biopsies were performed as needed. Analyses were based on 112 women with 224 paired samples and completed questionnaires. The overall HPV prevalence was 68.7% (95% CI, 59.377.2) with the S-Wet technique, 54.4% (95% CI, 44.863.9) with the S-Dry technique, and 53.8% (95% CI, 43.863.7) by HC. Overall agreement between the paired S-Wet and S-Dry samples was good (85.7%; 95% CI, 77.891.6), and kappa statistic was 0.70 (95% CI, 0.530.88). Positive agreement for type-specific HPV was 77.3% (95% CI, 68.284.9). In addition, no statistically significant differences were observed among the three techniques in terms of their sensitivity for cervical

Cervical screening has reduced the incidence and mortality of cervical cancer in Western countries, but it remains an issue in developing countries. Self-sampling for human papillomavirus (HPV) infection has been suggested as a means of resolving cost and availability concerns, but the use of a liquid medium for specimen collection risks spillage and medium availability may be problematic in under-resourced countries. The recent report that self-collection of cervical samples using dry vaginal swabs has comparable efficacy to self-collection of samples in liquid medium and physician-collected samples is thus a welcome development. In the study, 120 women attending a colposcopy clinic were assigned to collect two consecutive self-samples using a dry swab (S-Dry) and a wet transport medium (S-Wet), in random order. The samples were tested for HPV using real-time poly-

intraepithelial neoplasia grade 1 or higher lesions. Both the S-Wet and S-Dry tests were rated acceptable. Dry vaginal swabs thus appear to be a feasible option for self-screening for HPV.
Eperon I et al. Randomized comparison of vaginal self-sampling by standard vs. dry swabs for human papillomavirus testing. BMC Cancer 2013;13:353.

Vaginal vitamin C effective prophylactic against recurrent bacterial vaginosis


Bacterial vaginosis affects approximately 29% of women of childbearing age. The aetiology of the disorder is unclear, but it is characterized by an alteration in the vaginal microflora and the replacement of Lactobacillus spp with anaerobic vaginal

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C group experienced a recurrence compared with those in the placebo group (16.2% vs 32.4%; P = 0.024). The vitamin C recipients also had a significantly lower risk of recurrence (odds ratio, 0.405; 95% CI, 0.1820.901). Moreover, Kaplan-Meier survival analysis indicated that the women had a greater probability of being free of relapse after 5 months of treatment (P = 0.039) and that this probability increased after 6 months of treatment ( P = 0.029). The researchers concluded that 6-month prophylactic treatment with vitamin C effectively halves the risk of recurrence of bacterial vaginosis.
Krasnopolsky et al. Efcacy of vitamin C vaginal tablets as prophylaxis for recurrent bacterial vaginosis: a randomised, double-blind, placebocontrolled clinical trial. J Clin Med Res 2013;5(4):309315

The risks of perinatal outcomes, such as low birth weight, shorter gestational age, and congenital malformations, are known to be increased among children conceived by assisted reproduction, but little is known about their long-term development. Now, researchers in Denmark have shown that children conceived via fertility treatments show comparable development to children conceived naturally, although induced ovulation is associated with a slightly increased risk of mental disorders. The prospective cohort study compared the risk of mental disorders among children born in Denmark between 1995 and 2003 to mothers older than 20 years, using information from the Danish National Health Registers; 33,139 children were conceived after fertility treatment and 555,828 children were spontaneously conceived. Follow-up was in 2012 when the children were aged 817.

netic disorders; conduct, emotional, or social disorders; and tic disorders.


Bay B et al. Fertility treatment and risk of childhood and adolescent mental disorders: register based cohort study. BMJ 2013;34(Jul 5):f397.

Incidence density and aetiology of acute febrile illnesses among children in Asia

PAEDIATRICS

Risks associated with in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) were low and comparable to those in spontane-

Low risk of mental disorders in children born by assisted reproduction

ously conceived children, except for a borderline significant increase in the risk of tic disorders (hazard ratio [HR], 1.40; 95% CI, 1.011.95; absolute risk, 0.3%). However, children born after ovulation induction (with or without intrauterine insemination) had low but significantly increased risks of any mental disorder (HR, 1.2; 95% CI, 1.111.31; absolute risk, 4.1%); autism spectrum disorders (HR, 1.2; 95% CI, 1.051.37; absolute risk, 1.5%); hyperkinetic disorders (HR, 1.23; 95% CI, 1.08 1.40; absolute risk, 1.7%); conduct, emotional, or social disorders (HR, 1.21; 95% CI, 1.021.45; absolute risk, 0.8%); and tic disorders (HR, 1.51; 95% CI, 1.161.96; 0.4%). No risk was systematically related to a specific drug or hormone treatment. The overall long-term development of children born after IVF/ICSI appears to be comparable to that of children conceived spontaneously. However, children born after induced ovulation appear to have a small increased risk of autism; hyperkiChildren living in tropical countries, such as those in the Asia-Pacific region, often experience acute febrile illnesses. Differential diagnosis of these illnesses and estimation of the disease burden in a region can be difficult because the presenting symptoms of these illnesses are similar. Recently, a multicentre study among children in the dengueendemic countries of Indonesia, Malaysia, Philippines, Thailand, and Vietnam identified chikungunya, Salmonella Typhi, and dengue as the most common causes of acute fever.

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Journal Watch

A cohort of 1,500 healthy children aged 214 years were followed up in a prospective, active fever surveillance study for a mean of 237 days during 20102011. Sera samples were collected from 289 participants (19.3%) who experienced at least one acute febrile episode and tested for dengue, chikungunya, hepatitis A, influenza A, leptospirosis, rickettsia, and S Typhi using commercial tests. The overall incidence density of acute fever was 33.6 (95% CI, 3037.8) per 100 person-years of follow-up. Serological analysis indicated that 57% of the febrile children were positive for at least one of the listed diseases with chikungunya (35%) and S Typhi (29.4%) being the most common. The overall incidence density of chikungunya and S Typhi was 10.8 (95% CI, 8.913.1) and 9.1 (95% CI, 7.311.2) per 100 person-years, respectively. The overall incidence density of dengue was 3.4 (95% CI, 2.44.8) per 100 person-years based on non-structural protein 1 (NS1) antigen positivity and 7.3 (95% CI, 5.79.2) based on serology. Not all cases of dengue were clinically diagnosed and some cases were misdiagnosed. Chikungunya, S Typhi, and dengue appear to be the most common causes of acute fever in the region. Laboratory confirmation is required for an accurate assessment of disease burden.
Capeding MR et al. Dengue and other common causes of acute febrile illness in Asia: an active surveillance study in children. PLOS Negl Trop Dis 2013;7(7):e2331.

infants who were not diagnosed with hypertrophic cardiomyopathy after an echocardiogram, foetal hyperinsulinism, rather than a K ATP channel mutation, was considered the likely mediating factor in the development of hypertrophic cardiomyopathy. Among the infants who required surgery, the only significant risk factor differentiating those with and without hypertrophic cardiomyopathy was a younger gestational age (36 vs 38 weeks; P = 0.02). However, birth weight approached statistical significance ( P = 0.063). Given the relatively common incidence of hypertrophic cardiomyopathy among infants with congenital hyperinsulinism, the researchers suggest that routine echocardiogram and electrocardiogram of such infants be considered, particularly for those with a murmur or respiratory distress.
Huang et al. Hypertrophic cardiomyopathy in neonates with congenital hyperinsulinism. Arch Dis Child Fetal Neonatal Ed 2013;98(4):F351F354.

reviewed the charts of all infants younger than 3 months who were treated at their institution over a 3.5-year period (February 2000 to May 2004). Hypoglycaemia was detected within the first week of life in 68 infants who were subsequently diagnosed with congenital hyperinsulinism, 25 of whom underwent an echocardiogram for a variety of indications including murmur, cardiomegaly, respiratory

Eating behaviours among young children positively associated with serum non-HDL cholesterol
The new focus on preventive care has led to numerous studies of early risk indicators of disorders such as cardiovascular disease among young children. Recently, one such study found that eating behaviours among young children were significantly associated with serum non-high-density lipoprotein (non-HDL) cholesterol, a surrogate indicator of cardiovascular risk. A total of 1,856 children aged 35 years were recruited to the cross-sectional study from primary care practices in Toronto, Canada, between 2008 and 2011. The parents of the children completed the Nutritional Screening Tool for Every Preschooler (NutriSTEP) questionnaire, and their responses were compared with laboratory analyses of non-fasting blood samples drawn from the children.

Hypertrophic cardiomyopathy in infants with congenital hyperinsulinism


Hypertrophic cardiomyopathy is a recognized complication in infants of diabetic mothers, but the disorder may be underreported among infants with congenital hyperinsulinism, say researchers from the Childrens Hospital of Philadelphia. In their retrospective study, the researchers

distress, and arrhythmia. Hypertrophic cardiomyopathy was identified in 10 of the 25 infants (40%), all of whom had been born large for gestational age and required a pancreatectomy for focal or diffuse hyperinsulinism after failed diazoxide and octreotide therapy. Eight of the 10 infants also underwent a genetic analysis, and all were found to have ATP-sensitive potassium (K ATP) channel mutations. Since K ATP channel mutations were also detected in the 13

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cantly associated with LDL cholesterol and apolipoprotein B levels, both of which were correlated with serum non-HDL cholesterol (correlation coefficients, 0.90 and 0.89, respectively; P < 0.001). The researchers concluded that eating behaviours may be more closely related to health outcomes than dietary intake, and may thus be an important target for interventions promoting cardiovascular health in young children.
Persaud et al. Association between serum cholesterol and eating behaviours during early childhood: a cross-sectional study. CMAJ 2013;185(11):E531E536.

selves and their children. Data from 148 children were evaluated; a carry-over effect was noted, and so data were compared for day 1 as well as across all 4 days. The mean VAS scores on day 1 and across all 4 days were as follows: tablet, 9.39 and 9.01; powder, 8.84 and 8.20; suspension, 8.26 and 7.90; syrup, 8.35 and 8.19. The mean scores for the tablet were significantly higher than those for the suspension on day 1 as well as across all 4 days; they were significantly higher than those for the powder and syrup on day 1. In addition, significantly more administrations were swallowed in full for the tab-

Small tablets, syrup preferred oral formulations among preschool children


Infants and preschool children are often administered oral medications in a liquid formulation, but these may have a bad taste and often require Among the 1,076 children with sufficient data for analysis, the mean ( SD) laboratory indices were as follows: non-HDL cholesterol, 2.8 ( 0.6) mmol/L; HDL cholesterol, 1.3 ( 0.3) mmol/L; low-density lipoprotein (LDL) cholesterol, 2.2 ( 0.6) mmol/L; total cholesterol, 4.1 ( 0.7) mmol/L; apolipoprotein A1, 1.3 ( 0.2) g/L; and apolipoprotein B, 0.6 ( 0.1) g/L. The eating behaviours subscore of the NutriSTEP questionnaire was significantly associated with the serum non-HDL cholesterol level ( P = 0.03), and for each unit increase in this score, serum levels of non-HDL cholesterol were increased by 0.02 mmol/L (95% CI, 0.0020.05). The association between eating behaviours and serum non-HDL cholesterol level persisted after adjusting for age, sex, birth weight, z score body mass index, parental body mass index, gestational diabetes, and parental ethnicity. No other subscales of the nutritional questionnaire were associated with serum non-HDL, including dietary intake. However, the eating behaviours subscore was also signifirefrigerated storage. In an attempt to determine the optimal formulation among children and their parents, researchers from The Netherlands studied the acceptability of a placebo with a neutral taste administered as a small tablet, a syrup, a suspension, and a powder. They report that the tablets and syrup were preferred by both the parents and their children, and that intake was higher with the tablets. In the randomized cross-over study, an oral placebo was administered twice a day to 183 children aged 14 years at home by a parent in the form of a small tablet (< 4 mm diameter), a syrup, a suspension, and a powder. The formulations were administered on four consecutive days, but the parents were allowed to skip a day if necessary. Acceptability was assessed by score on a 10-cm Visual Analogue Scale (VAS) and by parental report of whether the dose was swallowed in full, in part, or not at all. At the end of the study, the parents also reported the formulation preferred by them-

let (1.96) compared with the powder (1.58), suspension (1.70), and syrup (1.67) formulations. Both the parents and their children preferred the tablet and syrup formulations.
Van Riet-Nales et al. Acceptability of different oral formulations in infants and preschool children. Arch Dis Child 2013;98:725731.

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GYNA GYNAECOLOGY ECOLOGY

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Prevention and Treatment of Autism Spectrum Osteoporosis in Women:Disorders An Update


Patricia Howlin, BA MSc PhD FBSP, Professor of Clinical Child Psychology Anna Daroszewska, MRCP(UK), FRCP Edin, PhD

INTRODUCTION
Owing to significant advances in biomedical research, women enjoy better health and live longer than ever before. As life expectancy increases, larger numbers of women reach old age, and paradoxically more and more women suffer from age-related chronic diseases, such as osteoporosis. It is estimated that osteoporosis currently affects approximately 200 million women worldwide. Osteoporosis is the most common metabolic bone disease. Over 2 million women in the United Kingdom have osteoporosis, and a woman aged 50 has an approximately 50% lifetime risk of suffering an osteoporotic fracture. The cost of osteoporotic fractures in the UK has been estimated at 2.3 billion in 2011 and predicted to increase to over 6 billion per year over the next 25 years. Approximately 80% of this cost relates to hip fractures, which carry the highest morbidity and mortality: 10% of patients die within a month and 33% within a year, 25% lose the ability to live independently, up to 50% have permanently impaired mobility, and only 30% make a full recovery. Osteoporosis is characterized by low bone mass and deterioration in bone architecture, which predispose to fragility fractures. Bone mineral density (BMD) is the most important predictor of fracture risk and is highly heritable with heritability estimates of 0.600.90. To date, dozens of genes and loci associated with osteoporosis have been identified by genome-wide association studies. Other contributing factors to bone strength, some of which are heritable, include bone turnover, bone architecture, and skeletal geometry (eg, long femoral necks fracture easier than short ones). The risk of falls, which depends on postural stability, frailty, rate of response, padding, and environmental factors, also contributes to fracture risk. Thus, the 10-year hip fracture probability (averaged for age and gender) varies between geographical regions and countries,
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with the highest in Scandinavia, lowest in South America and Asia, and the UK in between. Bone is a dynamic tissue, which undergoes renewal in the process known as the bone remodelling cycle, which, in physiological conditions, is initiated by bone-resorbing cells (osteoclasts). Osteoclasts secrete hydrochloric acid and cathepsin K, which dissolve bone mineral and collagen, respectively. Bone resorption is followed by osteoblastic bone formation whereby osteoblasts lay new bone matrix, which then undergoes mineralization. Osteoclast and osteoblast function is coupled owing to bidirectional communication. At a molecular level, osteoclastogenesis and consequently bone resorption are initiated by the stimulation of the receptor activator of nuclear factor-B (RANK), expressed on preosteoclasts, with its ligand (RANKL), expressed by osteocytes, osteoblasts, bone marrow stromal cells, and T and B lymphocytes. An endogenous soluble RANKL-decoy receptor, osteoprotegerin inhibits this process by binding to RANKL. Osteoblast differentiation and bone formation are triggered by the activation of the Wnt-signalling pathway, which leads to nuclear accumulation of -catenins. This process is mainly controlled by two naturally occurring Wnt-antagonists: sclerostin expressed by osteocytes and dickkopf-1 (Dkk-1) mainly expressed by osteoblasts and osteocytes. Understanding of these signalling pathways has lead to the development of novel treatments for osteoporosis (see below). The major contributing factor to bone loss after the menopause is the drop in oestrogen concentration by approximately 75%, which induces expression and production of RANKL. A similar effect is seen with therapeutic inhibition of oestrogen in women treated for receptor-positive breast cancer. High RANKL activity is also observed in certain autoimmune and malignant bone disorders, such as rheumatoid arthritis, periodontal disease, multiple myeloma, and osteolytic bone metastases. As a
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consequence, bone remodelling becomes disrupted such that there is a significant increase in bone resorption with slower uncoupled bone formation, which leads to poor bone repair, accumulation of micro damage, and ultimately weakening of bone with propensity to fracture. Thus, pharmacological treatment of osteoporosis involves either suppression of bone resorption with antiresorptive treatment, or stimulation of bone formation with anabolic agents, the former approach being currently most commonly used. Age- and pathology-related bone loss is frequently asymptomatic, and often osteoporosis is diagnosed only after a fragility fracture has occurred. In addition, drug-induced bone loss (Table 1) has been identified as a risk factor for osteoporosis. Thus, a high index of suspicion is needed to make the diagnosis early especially in women at high risk in order to prevent the first fracture. Bone mineral density can be measured with dual emission X-ray absorptiometry, and the World Health Organization defines osteoporosis by a Tscore of less than 2.5, ie, more than 2.5 standard deviations below the average BMD of a young woman. Osteopenia is defined by a T-score between 1 and 2.5. These definitions apply to peri- and postmenopausal women. In premenopausal women, there is a less clear relationship between T-scores and fracture risk, therefore it is recommended that BMD is assessed by Z-score (which is age-correlated). Thus, a Z-score equal to or below 2 defines BMD below the expected range for age, whereas a Z-score above 2 is in keeping with BMD within the expected range for age. The diagnosis of osteoporosis in premenopausal women, however, can be made in the presence of a fragility fracture. A number of national and international guidelines have been developed for the diagnosis and management of postmenopausal osteoporosis and primary and secondary prevention of osteoporotic

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Table 1. Drugs associated with osteoporosis and/or fragility fractures

Drug class Anticonvulsants Anti-retroviral drugs

Example Phenytoin Tenofovir

Indication Epilepsy HIV infection

Main mechanism of bone loss Increased liver hydroxylation of 25(OH)D to inactive metabolites Class-dependent effects on bone cells, PTH, vitamin D, and phosphate Low E-induced bone loss Increased bone resorption Suppressed bone formation Low E-induced bone loss Increased bone resorption and decreased bone formation Low E-induced bone loss Reduced acid-dependent absorption of calcium Unclear, but mediated through inhibition of 5-HTT in bone cells Shift from osteoblastogenesis to adipogenesis at progenitor level Increased bone resorption mediated by activation of TR on bone cells

Aromatase inhibitors Calcineurin inhibitors Glucocorticoids GnRH agonists Heparin (unfractionated) Progesterone Protein pump inhibitors Selective serotonin re-uptake inhibitors Thiazolidinediones Thyroid hormone

Letrozole Cyclosporin A Prednisolone Buserelin

Breast cancer Organ transplantation Autoimmune diseases Endometriosis Thromboembolic disease

Depot-medroxyprogesterone acetate Omeprazole Citalopram Rosiglitazone Levothyroxine

Contraception Peptic ulcer disease Depression Type 2 diabetes mellitus Hypothyroidism

GnRH = gonadotropin-releasing hormone; E = oestrogen; HIV = human immunodeciency virus; 5-HTT = 5-hydroxytryptamine transporter; 25(OH)D = 25-hydroxyvitamin D; PTH = parathyroid hormone; TR = thyroid hormone receptor .

fractures. In addition, the Fracture Risk Assessment Tool (FRAX) and the guidelines of the National Osteoporosis Guideline Group are valuable aids in making treatment decisions, and both are accessible online (www.shef.ac.uk/FRAX). FRAX is an al-

tion, femoral neck BMD can be entered, which has been shown to correlate well with the risk for hip and other fractures.

NON-PHARMACOLOGICAL gorithm, which provides assessment of the 10-year MANAGEMENT STRATEGIES


risk of fractures for different countries. FRAX takes into account several risk factors for fragility fractures, such as age, low body mass index (BMI), prior fragility fractures, parental history of hip fracture, smoking, daily alcohol intake of over 3 units, use of oral glucocorticoids, rheumatoid arthritis, and other causes of secondary osteoporosis. In addiPeak bone mass is reached during the third decade of life and is a key predictor of osteoporotic fractures at older age. The attainment of peak bone mass is determined by the interplay of several factors including the genetic programme, which cannot be altered, but also modifiable elements such as a
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healthy, varied, balanced, and nutritious diet with optimum protein, calcium, and vitamin D intake, hormonal status, and skeletal mechanical loading achieved through regular exercise. There is evidence to suggest that low-rate, age-related bone loss may begin after the age of 30 in both women and men in parallel to a decline in muscle mass. Thus, maintaining a healthy lifestyle is of paramount importance and should include cessation of smoking and reducing excessive alcohol intake. High sodium and/or caffeine intake promotes urinary calcium excretion and should be avoided. In contrast, vegetables and fruits contain potassium, which antagonizes urinary calcium excretion, and their intake should be encouraged. Low BMI is a risk factor for osteoporosis. However, obesity, which has been associated with a higher rate of vitamin D insufficiency, may also predispose to fragility fractures; thus, maintenance of an ideal BMI should be encouraged. Secondary causes of low bone mass require treatment, and medications associated with an increased risk of osteoporosis and/or fractures (Table 1) need to be reviewed and altered if possible. Single- and multifactorial fall prevention strategies have been shown to reduce the risk of falls in elderly women living in the community. These include assessment of risk factors such as poor mobility, medication inducing dizziness or hypotension, postural hypotension, poor vision, feet problems, inadequate footwear, hazardous household environment with regard to tripping hazards, and fear of falling. Targeted interventions involve exercise programmes, education, and correction of risk factors, with input from a multidisciplinary team involving physiotherapists, nurses, general practitioners, ophthalmologists, and occupational therapists. However, application of these strategies to nursing homes residents has been less successful. There has not been a consistent benefit found
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from the use of hip protectors in the elderly.

CALCIUM AND VITAMIN D


Prolonged low calcium intake causes a negative calcium balance with a compensatory increase in parathyroid hormone (PTH)-mediated bone resorption, which, at a younger age results in attainment of low peak bone mass, later increases age-related bone loss and, in postmenopausal women, contributes to osteoporosis. According to the US Institute of Medicine (IOM), the recommended daily dietary calcium allowance is 1,300 mg in adolescents and 1,000 mg in women until the age of 50, with the tolerable upper level (UL) intake of 3,000 mg and 2,500 mg, respectively. The recommendations are exactly the same for pregnant or lactating women in the respective age groups. The recommended daily calcium allowance and the UL for postmenopausal women are 1,200 mg and 2,000 mg, respectively. If these requirements are not met by diet alone (as assessed by dietary questionnaires), calcium supplementation should be considered. Vitamin D is synthesized in the skin during exposure to the UVB light, but many factors, such as latitude, overcast sky, skin pigmentation and ageing, clothing, and the use of sun blocks diminish this process. The main dietary sources of vitamin D are oily fish; however, an average diet alone provides only approximately 1020% of vitamin D requirement. Vitamin D status is best assessed by measuring the serum level of the metabolite 25-hydroxyvitamin D [25(OH)D]. Although there is no consensus regarding normal levels of 25(OH)D, most authorities agree that the optimum level of 25(OH) D for bone health is between 75 nmol/L (30 ng/mL) and 100 nmol/L (40 ng/mL), as at this level the PTH is at its nadir, intestinal calcium absorption at its optimum, the risk of falls is least with greatest frac-

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ture prevention, and there are no detectable bone mineralization defects present. It has been estimated that approximately 1 billion people may be affected by vitamin D deficiency [defined as serum level of 25(OH)D below 25 nmol/L (10 ng/mL)] or insufficiency [serum level of 25(OH)D of 2575 nmol/L (1030 ng/mL)]) worldwide, and more than half of women with postmenopausal osteoporosis receiving treatment may have suboptimal levels of vitamin D. As vitamin D receptor is widely expressed and many tissues possess 1 -hydroxylase activity [necessary for conversion of 25(OH)D to the active metabolite 1.25(OH)2D], it comes as no surprise that vitamin D deficiency has been linked not only to osteoporosis, osteopenia, and osteomalacia, but also propensity to falls due to weakening of the muscles, and many other disorders including autoimmune, cardiovascular, neoplastic, mental, and infectious diseases. The IOM recommends a vitamin D dietary daily allowance of 600 international units (IU), increasing to 800 IU after the age of 70 with the UL of 4,000 IU, assuming minimal sun exposure. However, the Endocrine Society has recently published guidelines suggesting a higher daily vitamin D intake for patients at risk of vitamin D deficiency: for adolescents 6001000 IU, and for women over the age of 19 between 1,5002,000 IU, with an UL of 4,000 IU and 10,000 IU, respectively. The same recommendations apply to pregnant and lactating women in the respective age groups. The effect of calcium and vitamin D supplements (alone or in combination) on BMD and fracture risk has been studied extensively with inconsistent results, possibly due to different methodology, diet, sun exposure, and bioavailability of the compounds used. A randomized controlled trial (RCT) of over 3,000 healthy ambulatory elderly women from residential homes and sheltered accommodation, who were given 800 IU of vitamin D3 and 1.2 g calcium or a

double placebo for 18 months, has shown a 2.7% increase in the hip BMD, a 43% reduction in hip fractures, and a 32% reduction in non-vertebral fractures in the treatment group. A meta-analysis of 29 RCTs involving over 60,000 men and women over the age of 50 demonstrated an overall 12% reduction in fracture risk, which increased to 24% in trials with high compliance rate with calcium and vitamin D supplementation. The best effect was seen with 800 IU of vitamin D, or more, and 1.2 g calcium, or more per day. However. a Cochrane meta-analysis of 10 trials assessing the role of vitamin D alone and eight trials assessing the role of vitamin D and calcium in fracture prevention failed to show an association between vitamin D supplementation alone and fracture prevention, but confirmed a modest reduction in fracture risk with vitamin D and calcium supplementation in the elderly (OR, 0.89; 95% CI, 0.800.99). Controversy remains with regard to a possible association between calcium supplementation and an increased risk of cardiovascular disease, reported by some but not by others, and not confirmed by prospective randomized trials with cardiovascular events taken as the primary end point.

HORMONE REPLACEMENT THERAPY


Accelerated bone loss in women occurs at menopause and continues for up to 510 years after the cessation of menses. There is evidence that increased bone loss associated with decreasing serum oestradiol and increasing follicle-stimulating hormone may start already 23 years prior to the last menses. Oestrogen deficiency causes a high bone turnover state, characterized by acceleration of both bone resorption and formation; however, as the relative activity of osteoclasts is greater than osteoblasts, the net effect is bone loss. Thus,
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suppression of osteoclast activity by oestrogen replacement (hormone replacement therapy [HRT]) has been used effectively for decades and was the mainstay of prevention and treatment of osteoporosis in postmenopausal women well before the use of bisphosphonates. The Womens Health Initiative (WHI) study of over 16,000 postmenopausal women, examining health benefits and risks of one HRT regimen (conjugated equine oestrogen 0.625 mg/d and medroxyprogesterone acetate 2.5 mg/d), established that combined HRT reduced the risk of vertebral, hip, and other osteoporotic fractures by 34%, 34%, and 23%, respectively. However, it was estimated that for the prevention of five hip

menopause until the age of around 50 in order to avoid bone loss and can be used for treatment of postmenopausal osteoporosis until the age of 60 in the absence of risk factors for breast cancer, cardiovascular, and thromboembolic disease. The risks and benefits of HRT should be clearly explained to the patient. HRT is not considered suitable for women over the age of 60. Withdrawal of HRT results in bone loss. There is conflicting evidence with regard to the fracture risk as some data suggest an immediate increase, whereas other favour a prolonged protective effect.

SELECTIVE OESTROGEN RECEPTOR fractures (and six colon cancers), an additional MODULATORS
eight breast cancers, seven coronary heart disease events, eight cerebrovascular events, and eight pulmonary emboli emerged per 10,000 women-years exposure to HRT, and therefore the study had to be prematurely discontinued in 2002 after just over 5 years. Another WHI study of over 6 years duration of unopposed oestrogen replacement in over 10,000 postmenopausal women with prior hysterectomy confirmed a reduction in hip and vertebral fractures by nearly 40%, but also demonstrated an increased risk for strokes, although suggested a decreased risk for breast cancer. Subsequently, the Medicines and Healthcare Products Regulatory Agency (MHRA) advised that HRT should no longer be the treatment of choice for prevention of osteoporosis in women over the age of 50, and treatment preferences shifted towards the use of bisphosphonates. However, recent evidence suggests that in the early postmenopausal women, the benefits of using HRT may outweigh the risks, and in the wake of recently emerging concerns relating to long-term use of bisphosphonates, HRT seems to be coming back into favour. Recently, the National Osteoporosis Society has published a position statement advising that HRT should be recommended for women with early
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Selective oestrogen receptor modulators (SERMs) are compounds, which, in general, act as oestrogen agonists on bone and oestrogen antagonists on breast and brain tissue. The effect on the uterus can be neutral, as seen with raloxifene, or antagonistic in the presence of oestrogen, as seen with bazedoxifene. The Multiple Outcomes of Raloxifene Evaluation (MORE) study demonstrated a 30% vertebral (but not non-vertebral) fracture risk reduction in postmenopausal women treated with raloxifene 60 mg/d for 3 years. No effect on nonvertebral fracture risk reduction was seen in the 4-year Continuing Outcomes Relevant to Evista (CORE) study either. The 5-year long placebo-controlled Raloxifene Use for The Heart (RUTH) study of over 10,000 postmenopausal women at risk of coronary heart disease also showed a 35% reduction in clinical vertebral fracture risk, but no effect on non-vertebral fractures. Raloxifene, like oestrogen, suppresses bone turnover, however, to a lesser degree. In addition, raloxifene can increase menopausal symptoms, especially hot flushes, and is associated with an increased risk of thromboembolic events. Consequently, raloxifene is usually

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prescribed to asymptomatic postmenopausal women with a relatively low spinal BMD as compared with hip BMD and in the absence of risk factors for thromboembolic disease. Raloxifene has recently been approved for prevention of breast cancer, which may extend its use to postmenopausal women in that risk category. However, raloxifene is contraindicated in pre-menopausal women, as it competes with oestrogen and blocks its action on bone with consequent bone loss. The National Institute for Health and Clinical Excellence (NICE) recommends raloxifene in secondary (but not primary) prevention of osteoporotic fractures in postmenopausal women with contraindications or intolerance to bisphosphonates. The recently reported outcome of the Postmenopausal Evaluation and Risk Reduction with Lasofoxifene (PEARL) study of over 8,000 women showed that 0.5 mg/d of lasofoxifene reduced the risk of vertebral fractures by 42% at 3 years and non-vertebral fractures (but not hip) by 24% at 5 years, in addition to reducing risk of oestrogen receptor-positive breast cancer, coronary heart disease, and stroke, but, like raloxifene, increased risk for venous thromboembolic events, vasomotor symptoms, and leg cramps. There was also an increased risk for uterine polyps and endometrial hypertrophy reported but no increased risk for endometrial cancer or hyperplasia. In a 3-year study of nearly 7,000 postmenopausal women, another SERM, bazedoxifene, has been shown to reduce vertebral fractures by approximately 40% and non-vertebral fractures by about 50%, the latter only in a subgroup of women at high fracture risk and according to a post hoc analysis. Bazedoxifene did not show any stimulatory effect on the endometrium but was associated with increased vasomotor symptoms, leg cramps, and deep vein thrombosis. Both lasofoxifene and bazedoxifene have been approved for use in postmenopausal osteoporosis in the EU.

In order to improve the side effect profile of SERMs and HRT, a novel tissue selective oestrogen complex (TSEC) therapy is under development. A randomized, double-blind placebo-controlled phase III trial, involving over 3,000 postmenopausal women, demonstrated that TSEC containing bazedoxifene and conjugated oestrogens given for 2 years preserved BMD, reduced vasomotor symptoms, and protected endometrium from the stimulatory action of unopposed oestrogens. The long-term effect of TSEC therapy on fracture prevention is currently unknown.

BISPHOSPHONATES
Bisphosphonates are the most widely used antiresorptive agents for treatment of osteoporosis and have been in clinical use since the late 1960s. Bisphosphonates are synthetic analogues of naturally occurring inorganic pyrophosphate, but instead of a POP bond they contain a PCP bond, which is highly resistant to hydrolysis. The carbon atom in the PCP bond is also bonded to side chains, known as R1 and R2, which, depending on the structure and the presence of the nitrogen atom, account for different binding affinity and potency of different agents. Bisphosphonates bind strongly to mineral especially at sites of active bone remodelling, where they are then taken up by bone-resorbing osteoclasts. The most potent bisphosphonates are nitrogen-containing (amino-) bisphosphonates (alendronate, risedronate, ibandronate, pamidronate and zoledronate), which inhibit the farnesyl pyrophosphate (FPP) synthase, an enzyme in the mevalonate pathway, and prevent prenylation of small guanosine triphosphate (GTP)-binding proteins (GTPases), which are essential for osteoclast function and survival. Non-nitrogen containing bisphosphonates (etidronate, tiludronate, and clodronate) are metabolized to cytotoxic ATP analogues, which induce osJPOG SEP/OCT 2013 187

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teoclast apoptosis. Thus, bisphosphonates reduce bone turnover, allowing for more complete mineralization of existing (but reduced) bone tissue mass, which is reflected in an increase in BMD observed in clinical trials; however, they do not increase bone tissue mass per se (in contrast to anabolic agents). Bisphosphonates can be given orally or intravenously. As absorption of bisphosphonates given orally in ideal conditions is less than 1%, the dose has to be administered with plain water only, after an overnight fast, and followed by 3060 minutes with nothing else by mouth. In addition, patients must remain upright afterwards in order to prevent any gastro-oesophageal reflux (see below). Approximately 50% of the absorbed dose binds to bone and 50% is excreted by the kidneys. As bisphosphonates bound to bone persist in the skeleton for months or years, they should be used with caution in pre-menopausal women of childbearing potential and avoided in pregnancy. Animal studies have shown that bisphosphonates cross the placenta and accumulate in the foetal skeleton. However, their effect on the human fetus is unknown, and normal pregnancy outcomes have been reported in women treated with bisphosphonates before and during pregnancy. Bisphosphonates are effective in women in prevention of bone loss due to ageing, oestrogen deficiency, and corticosteroid use, and in prevention of fractures in postmenopausal and steroid-induced osteoporosis. Currently, the most commonly used bisphosphonates are the amino-bisphosphonates, whose anti-fracture efficacy has been demonstrated in a number of randomized, placebo-controlled trials. Alendronate, risedronate, ibandronate, and zoledronate reduce the risk of vertebral fractures in women with postmenopausal osteoporosis by 4070% over a 3-year period of time compared with placebo. Alendronate, risedronate, and zoledronate,
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in addition, reduce the risk of non-vertebral and hip fractures. However, ibandronate has been shown to reduce the risk of non-vertebral fractures only in a subgroup of women at high risk of fractures and has not been proven to reduce the risk of hip fractures. Currently, the bisphosphonate of choice in prevention and treatment of osteoporosis is alendronate owing to its proven efficacy and low cost. Risedronate has a slightly better side effect profile with regard to oesophageal irritation according to some studies and can be substituted for alendronate if necessary. Both alendronate and risedronate are typically given once a week. The most common side effects of oral bisphosphonates are symptoms of oesophageal irritation, abdominal pain, and nausea. Patients who are intolerant of oral bisphosphonates can be treated with intravenous bisphosphonates such as ibandronate, or zoledronate, administered 3-monthly and once a year, respectively. The main side effect of amino-bisphosphonates given intravenously is an acute phase reaction (fever, myalgia, lymphopenia, elevated Creactive protein), which may occur in over 50% of patients after the first infusion, and is due to the release of pro-inflammatory cytokines (tumor necrosis factor , interferon , and IL-6) by an activated subset of -T cells. In vitro studies have shown that peripheral blood monocytes (which, like osteoclasts, originate from the monocytemacrophage lineage) accumulate the isopentenyl pyrophosphate (IPP), a metabolite upstream of FPP synthase, when exposed to amino-bisphosphonates and activate a subset of -T cells by cell-to-cell contact. However, co-administration of statins (which inhibit an enzyme upstream of FPP synthase and prevent accumulation of IPP) has failed to prevent the acute phase reaction in patients receiving intravenous bisphosphonates so far. Thus, acetaminophen remains the treatment of choice for the acute phase reaction and is given until the symptoms subside,

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typically for 2 or 3 days. The acute phase reaction is less common and milder with subsequent bisphosphonate infusions. Hypocalcaemia may occur, and although usually mild it is important to ensure that patients are vitamin D replete prior to giving bisphosphonates especially if using the parenteral route. Bisphosphonates are eliminated through renal excretion, and manufacturers do not recommend their use if creatinine clearance is less than 3035 mL/min owing to lack of clinical experience, although studies have shown that they can be safely given orally to the elderly with renal impairment under certain circumstances. There is low risk of acute renal failure in patients receiving intravenous bisphosphonates, which can be reduced further by adequate hydration prior to the infusion. An increased risk of atrial fibrillation (AF) has been reported in the Health Outcomes and Reduced Incidence with Zoledronic acid once yearly Pivotal Fracture Trial (HORIZON-PFT), however, not confirmed in the subsequent HORIZON Recurrent Fracture Trial. Whilst a non-significant trend toward an increase in AF was observed in the alendronate Fracture Intervention Trial (FIT), no such effect was seen in the Vertebral Efficacy with Risedronate Therapy (VERT) trial. A recent meta-analysis of RCTs and case-control studies of bisphosphonate use recognized a possible link with AF but failed to draw definitive conclusions with regard to risk, owing to heterogeneity of evidence. A number of cases of oesophageal cancer in bisphosphonate users have been recently reported, suggesting a causative link; however, because of lack of information regarding risk factors for oesophageal cancer in these patients, expected incidence, and lack of a control group, the potential association has been questioned. Indeed, other reports using large European and US clinical data registries failed to show an association; therefore,

a causative link has not been confirmed so far. Recently, concerns have been raised regarding bisphosphonate-induced decrease in bone remodelling and bone repair in relation to osteonecrosis of the jaw (ONJ) and atypical subtrochanteric fractures. ONJ is defined as exposure of necrotic bone in the oral cavity, not healing for 68 weeks. ONJ was originally linked to bisphosphonate use in 2003, when it was identified in a number of patients who had received high doses of intravenous bisphosphonates for skeletal complications of malignancy. In such patients, ONJ can occur in up to 15% of cases. In women with postmenopausal osteoporosis treated with bisphosphonates, rare cases of ONJ have been reported; however, the estimated risk is very low, in the range of 1:160,000 worldwide, and the causal association is unproven. ONJ can be spontaneous but is often precipitated by trauma, such as tooth extraction or other dental procedures. Thus, patients should be advised to complete any planned dental procedures before starting bisphosphonate treatment and maintain good oral hygiene. Over the last few years, a number of atypical low-trauma subtrochanteric and femoral shaft fractures have been reported in patients receiving long-term bisphosphonates. Frequently, these patients reported prodromal symptoms of pain in the region of the pending fracture (typically groin or thigh). Characteristic radiographic finding of an impending atypical fracture was thickening of the cortex in the lateral aspect of the proximal femur, which is the site of high tensional stresses. A completed atypical fracture displayed, in addition, a straight transverse fracture line and medial cortical spiking. These reports raised concerns about over-suppression of bone remodelling and repair by long-term use of bisphosphonates, which could allow for accumulation of microcracks over time and predispose to fatigue fractures. A recent Swedish population-based nationwide analysis of over
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There have been concerns about the association of long-term bisphosphonate use with atypical femoral fractures.

year) after discontinuation of the bisphosphonate. It is currently unclear how long bisphosphonates should be continued for. In the Fracture Intervention Trial (FIT) Long-Term Extension (FLEX) Trial, 10 years of alendronate significantly reduced the incidence of new clinical vertebral fractures but not morphometric vertebral fractures or non-vertebral fractures as compared with 5 years of alendronate. However, a significant reduction of non-vertebral fracture risk was observed in a subgroup of women with a femoral neck T-score of 2.5 or lower (RR, 0.50; 95% CI, 0.260.96) as compared with women with higher femoral neck T-scores, suggesting that women who remain at high risk of osteoporotic fractures after 5 years treatment with alendronate would benefit from an additional 5 years of treatment. The recently extended 3-year zoledronate HORIZON-PFT trial demonstrated prolonged effect on BMD lasting for up to 3 years after discontinuation of zoledronate; however, significantly less morphometric vertebral fractures were seen in women treated for 6 years. At the time of writing, there is an ongoing debate in the field with regard to long-term bisphosphonate use primarily driven by limited evidence; however, most authorities suggest treatment with bisphosphonates for 510 years, depending on patients fracture risk, and withdrawal of treatment for 12 (up to 5 years) or until there is significant

13,000 women over the age of 55, who sustained a femoral fracture in 2008, revealed that out of over 1,200 women who suffered a subtrochanteric or femoral shaft fracture, 59 fractures were atypical. The age-adjusted relative risk (RR) of atypical fracture in bisphosphonate users was 47.3 (95% CI, 25.687.3), confirming the association; however, the absolute increase in risk was small, only five cases per 10,000 patient-years (95% CI, 47). The risk was independent of co-morbidities and use of other drugs and rapidly diminished (by 70% per
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loss of BMD or the patient has a fracture, whichever comes first. If after 10 years of treatment, fracture risk remains high, some consider an interval treatment with raloxifene or teriparatide.

CALCITONIN
Calcitonin, a peptide hormone produced by the C cells of the thyroid gland, has an antiresorptive effect, which is mediated through calcitonin receptors abundant on osteoclasts. The salmon calciton-

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in, which is used in the treatment of osteoporosis, is approximately 2040 times more potent than human calcitonin. It is administered intranasally at a dose of 200 units per day (to alternate nostrils) and is generally well tolerated, although flushing, nausea, diarrhoea, and local irritation can occur. Calcitonin administered as nasal spray at 200 units a day has been shown to reduce the risk of vertebral fractures by 33% over 5 years in a placebocontrolled study. However, no effect was shown on non-vertebral fracture rate. Calcitonin can be used in patients with osteoporosis and renal impairment in whom bisphosphonates are contraindicated.

significantly greater suppression of bone turnover markers in patients treated with denosumab. However, after denosumab discontinuation, a rebound effect of rapid increase of bone turnover markers and decline in BMD is observed, in keeping with a relatively short offset of action in comparison with bisphosphonates, which can persist in the skeleton for years. Denosumab has a good safety profile, with clinical data available for over 8 years of use. In the phase III FREEDOM trial, a higher number of cases with cellulitis were reported in patients taking denosumab as compared with placebo (0.3% vs < 0.1%), although the absolute risk was very low. In patients receiving denosumab for treatment of postmenopausal osteoporosis not unlike with bisphosphonates, rare cases of ONJ have been reported; but so far, there have been no reports of atypical fractures.

DENOSUMAB
Denosumab is a novel fully human monoclonal antibody, which binds to RANKL and prevents RANKL from binding to RANK, thereby inhibiting osteoclastogenesis and osteoclast survival. Denosumabs half-life is approximately 26 days, and it is detectable in the system for several weeks. The usual dose is 60 mg given subcutaneously at 6-monthly intervals. As the clearance of denosumab occurs through the reticuloendothelial system and not through renal excretion, denosumab can be given to patients with renal impairment. The FREEDOM trial, a 3-year randomized placebo-controlled trial of denosumab in the treatment of postmenopausal osteoporosis, revealed a significant reduction in vertebral, hip, and non-vertebral fracture risk of 68%, 40%, and 20%, respectively, when compared with placebo. Although no head-to-head trial comparing the effect of denosumab and bisphosphonates on fracture risk has been performed, two double-blind, randomized clinical trials evaluating the efficacy and safety of denosumab vs alendronate showed significantly greater increase of BMD at all measured sites in denosumab treated patients of approximately 1%. This increase in BMD corresponded to

STRONTIUM RANELATE
Strontium ranelate contains two atoms of strontium, which have a higher atomic number than calcium and ranelic acid. Strontium ranelate combines antiresorptive and anabolic activity and may dissociate bone resorption from bone formation, as suggested by decreased bone resorption markers and increased bone formation markers during treatment. The exact mechanism of action of strontium ranelate, however, remains to be elucidated. The Spinal Osteoporosis Therapeutic Intervention (SOTI) trial of strontium ranelate in the treatment of postmenopausal osteoporosis demonstrated a reduction of the risk of vertebral fractures by 49% in the first year and 41% after 3 years of treatment. An increase in the lumbar, femoral neck, and total hip BMD by 14.4%, 8.3%, and 9.8%, respectively, over 3 years was observed as well; however, it has been estimated that up to 50% of the BMD changes may be due to increased X-ray absorption of stronJPOG SEP/OCT 2013 191

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tium compared with calcium. The subsequent Treatment of Peripheral Osteoporosis (TROPOS) study also showed a reduction of non-vertebral fractures by 19%, and in the subgroup of women at high risk of hip fracture, there was a 36% reduction of the relative risk of hip fractures seen after 3 years of treatment. An open-label 5-year extension of the SOTI and TROPOS studies demonstrated continuous increase in BMD, anti-fracture efficacy, and safety of taking strontium ranelate for 10 years. Strontium ranelate is given orally at a dose of 2 g a day. It has to be administered after and followed by a 2-hour fast; thus, it is given last thing at night. Strontium ranelate is generally well tolerated, and the most common side effects include nausea and diarrhoea, which usually subside with continuous treatment. Mild and transient elevation in creatine kinase can occur. Strontium ranelate is contraindicated in patients with risk factors for thromboembolic disease in view of a small increase of venous thromboembolic events observed after pooling the SOTI and TROPOS trial data. Severe allergic reactions to strontium ranelate have been reported (including the drug reaction with eosinophilia and systemic symptoms [DRESS syndrome]); therefore, patients developing a rash must discontinue the treatment immediately. NICE recommends strontium ranelate as an alternative treatment to bisphosphonates in primary and secondary prevention of fractures in postmenopausal osteoporosis.

tide has the Food and Drug Administration approval in the US. Teriparatide administered as a 20-g subcutaneous injection daily has been shown to increase lumbar and femoral BMD by about 9% and 3%, respectively, over 21 months. There was a 65% and 54% fracture risk reduction seen in vertebral and non-vertebral sites as well. The number of hip fractures was lower; however, a significant fracture risk reduction was not seen, possibly because of small numbers. Teriparatide is licenced for use in postmenopausal osteoporosis. Teriparatide has been also shown in clinical trials to be of particular value in steroid-induced osteoporosis, which is characterized by suppressed bone turnover, in which state the anabolic action of teriparatide is of particular benefit. Teriparatide has also been shown to reduce pain associated with osteoporotic vertebral fractures. NICE recommends its use in patients with severe osteoporosis for secondary prevention of fractures in patients who are intolerant of, have contraindications to, or have an unsatisfactory response to bisphosphonates and/or strontium ranelate, and have a T-score of 4 or lower (or in patients with a T-score of 3.5 who had already sustained two fragility fractures). Administration of PTH peptides can rarely cause transient hypercalcaemia, which has been reported more commonly with PTH 1-84. PTH peptides are contraindicated in other metabolic bone diseases than osteoporosis, in patients with skeletal malignancy (in patients with a history of cancer, utmost caution is advised owing to reports of the presence of occult micrometastases in the bone marrow in many cancers including breast cancer and non-small-cell lung cancer), and in patients with a history of skeletal irradiation. Teriparatide should be given to patients who are vitamin D replete and is licenced to be used for 24 months, after which time an antiresorptive agent should be

PTH PEPTIDES
Intermittent administration of low-dose PTH has an anabolic effect on bone as it enhances osteoblast activity and bone formation in stark contrast to the action of antiresorptive agents. Two PTH derivatives have been approved for treatment of postmenopausal osteoporosis in Europeteriparatide (PTH 1-34) and PTH 1-84whereas only teriparaJPOG SEP/OCT 2013 192

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considered in order to maintain bone gain achieved with teriparatide treatment.

bar spine BMD by 5.5%. A phase III trial of over 16,000 postmenopausal women with osteoporosis is expected to be completed by July 2012. Results are also pending on the phase II trial of another cathepsin K inhibitor, ONO-5334. As inhibition of cathepsin K does not affect osteoclast viability, theoretically osteoclastosteoblast communication should be preserved allowing for uninterrupted new bone formation. It remains to be seen whether this concept translates into an advantageous clinical effect over the classic antiresorptives. Development of anabolic therapies has gained momentum as well. Calcilytic drugs are antagonists of the calcium sensing receptor in the parathyroid gland and their action mimics hypocalcaemia, causing a short pulse of PTH secretion (resembling the anabolic action of PTH peptides given by daily injections). Results of two phase II clinical trials on the most advanced oral compound in this class, MK5442, in postmenopausal osteoporosis are expected in 2012.

NEW DEVELOPMENTS
The use of combination therapy in treatment of postmenopausal osteoporosis has been addressed by several studies. The combined use of bisphosphonates and HRT overall results in greater increases in BMD than either therapy alone; however, owing to lack of evidence for greater fracture reduction, such regimens are generally not recommended. Treatment with bisphosphonates followed by strontium ranelate or PTH peptides initially blunts the BMD response, whereas studies of concurrent treatment with bisphosphonates and PTH peptides yielded conflicting results. Concurrent treatment with a single zoledronate infusion followed by daily PTH injections resulted initially in faster BMD increments than monotherapy. However, by 12 months, this effect was lost, and compared with combination therapy, PTH alone and zoledronate alone yielded similar BMD increase in the lumbar spine and femoral neck, respectively. Thus, zoledronate followed by treatment with PTH may be considered for women at high risk of femoral neck and other fractures. Antiresorptive therapy given after treatment with teriparatide maintains or increases the gains in BMD. Further research in this area is necessary to establish efficacy and safety of different regimens. Recent advances in the understanding of bone pathophysiology at a cellular and molecular level have allowed for development of novel treatments for osteoporosis, such as denosumab described above and already in clinical use. A number of other novel antiresorptive compounds, including cathepsin K inhibitors, are being investigated in postmenopausal osteoporosis. Odanacatib given for 24 months in a phase II trial increased the lum-

There is a need for more research... to understand the underlying mechanisms of bone loss leading to osteoporosis, so that novel treatments can be developed

Understanding of the pathophysiology of two rare conditions characterized by high bone mass, van Buchems disease and sclerosteosis, both due to inactivating mutations of the gene encoding sclerostin (endogenous inhibitor of the Wnt-signalling
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pathway in osteoblasts), has lead to the development of anti-sclerostin antibodies. In a phase I trial, a single 3 mg/kg subcutaneous dose of the anti-sclerostin antibody AMG 785 increased bone formation markers after 21 days by 60100% without affecting markers of bone resorption. Results of a phase II trial in postmenopausal women with low BMD comparing the effect of AMG 785, alendronate, and teriparatide are anticipated in August 2012.

K inhibitors, calcilytic drugs, and anti-sclerostin antibodies, are currently being assessed in clinical trials. There is a need for more research in order to understand the underlying mechanisms of bone loss leading to osteoporosis, so that novel treatments can be developed with an emphasis not only on suppression of bone resorption, which may lead to unwanted consequences long term, but on bone preservation and improvement of bone quality.

FURTHER READING CONCLUSIONS


In the ageing population, osteoporosis is a growing health problem and an increasing economic burden. Efforts to attain and maintain peak bone mass for as long as possible seem a logical approach and include a healthy lifestyle, nutritious and balanced diet with optimal calcium and vitamin D intake and physical exercise with skeletal mechanical loading. In addition, a plethora of pharmacological treatments is available for women with or at risk of osteoporosis or fragility fractures and can be targeted to the individual. Thus, HRT may be considered for women with early menopause and postmenopausal women until the age of 60 unless there are contraindications. SERMs may suit younger postmenopausal women at greater risk for vertebral fractures than hip fractures and/or intolerant of bisphosphonates. Bisphosphonates are recommended as first-line therapy; however, there have been concerns with regard to long-term safety, and their use is generally not recommended for longer than 10 years. For older patients intolerant of bisphosphonates, strontium ranelate is a good choice. Denosumab is a safe option in patients intolerant of or with contraindications to bisphosphonates and improves compliance. Anabolic therapy with PTH peptides is currently reserved for severe osteoporosis. A number of novel treatments, eg, cathepsin
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Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 2011;48:677692. Bolognese MA. SERMs and SERMs with estrogen for postmenopausal osteoporosis. Rev Endocr Metab Disord 2010;11:253259. Bowring CE, Francis RM. National Osteoporosis Societys Position statement on hormone replacement therapy in the prevention and treatment of osteoporosis. Menopause Int 2011;17:6365. Favus MJ. Bisphosphonates for osteoporosis. N Engl J Med 2010;363:20272035. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deciency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911 1930. National Institute for Health and Clinical Excellence (NICE). Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women, www.nice.org.uk/guidance/TA160; 2011. National Institute for Health and Clinical Excellence (NICE). Alendronate, etidronate, risedronate, raloxifene and strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women, www.nice.org.uk/guidance/ TA161; 2011. National Institute for Health and Clinical Excellence (NICE). Denosumab for the prevention of osteoporotic fractures in postmenopausal women, www.nice.org.uk/guidance/TA204; 2010. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet 2011;377:12761287. Rosen CJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. Washington: American Society for Bone and Mineral Research, 2008. 2012 Elsevier Ltd. Initially published in Obstetrics, Gynaecology And Reproductive Medicine 2012;22(6):162169.

About the Author


Anna Daroszewska is a Clinical Senior Lecturer and Honorary Consultant Rheumatologist at the Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

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Renal Disease in Pregnancy Perinatal Case Management Caring for Mothers as They Care for Babies
Matt Hall, MA, MB, MD, MRCP(UK); Nigel J Brunskill, MB, PhD, FRCP Chng Ying Chia, MA (Applied Social Studies); Jemie Biwen Wang, Bachelor of Psychology (Hons); Helen Chen, MBBS, M Med (Psych), Dip. Psychotherapy

INTRODUCTION
Chronic kidney disease (CKD) is defined as abnormalities in serum biochemistry, urinary constituents (blood and/or protein), or renal structure that are present for 3 months or more. The National Kidney Foundation K/DOQI classification of CKD divides CKD into five stages, dependent on the estimated glomerular filtration rate (eGFR) (Table 1). CKD is rare in pregnant patients, affecting 0.15% of pregnancies, and most affected patients have early stages of CKD (stages 13a; eGFR > 45 mL/min). Pregnancy may be the first time that blood pressure and urine analysis are performed for some women; hypertension, proteinuria, or haematuria detected at booking may uncover previously undiagnosed CKD. The development of hypertension and urinary dipstick abnormalities later in pregnancy may be a manifestation of CKD but more commonly represents preeclampsia. Chronic pyelonephritis is the commonest known aetiology of CKD in pregnant women (Figure 1).

RENAL PHYSIOLOGY IN NORMAL PREGNANCY


During normal pregnancy, the maternal cardiovascular system undergoes important changes. Blood volume and red cell mass increase by up to 50%, systemic vascular resistance falls, and cardiac output increases by up to 30%. These cardiovascular adaptations have profound effects on renal function:
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Table 1. National Kidney Federation K/DOQI classification of chronic kidney disease (CKD)

renal blood flow increases by 50%  glomerular filtration rate (GFR) increases by 30% serum creatinine decreases by 20% Blood pressure falls in the first two trimesters and gradually returns to baseline as the pregnancy approaches term. Increased GFR, changes in glomerular haemodynamics, and, possibly, alterations in renal tubular function lead to an increase in urine protein excretion in pregnancy from an upper limit of 150 mg/d to 260 mg/d. Renal size increases by approximately 1 cm in bipolar length during normal pregnancy. Smooth muscle relaxation and compression of the ureters by the gravid uterus commonly lead to pelvicalyceal dilatation, more prominently on the right than the left.

CKD stage Estimated GFR 1 2 3 > 90 mL/min 6089 mL/min 3059 mL/min

Comment Only classified as CKD if associated with renal structural or urinary dipstick abnormalities May be subclassified into: 3 a: 4559 mL/min  3b: 3044 mL/min

4 5

1529 mL/min < 15 mL/min or on dialysis

GFR = glomerular filtration rate. Estimated GFR calculations are not valid during pregnancy.

Figure 1. Aetiology of chronic kidney disease in patients presenting to renal-obstetric clinics in the UK.

The magnitude of these changes makes it unsurprising that limitation to adaptation by CKD can lead to adverse pregnancy outcomes.

25 20 Percentage 15 10 5 0
C Ot hron he ic r p py Sy rim el st ar one em y g ph ic lo rit Iu m is p Po us nep eru e lyc r h la ys ythe ritis r tic Co m kid ato n Ot gen su ne he i s r h tal r y dis en er e a ed a ita l dy se sp ry l r Re ena asia ld na ls i to sea Di se ne ab di et se ic as ne e ph ro pa th y Ot he Un r kn ow n

PREGNANCY IN WOMEN WITH CKD


Advice for women with CKD embarking upon pregnancy should focus on two issues: Will kidney disease affect the pregnancy? Will pregnancy affect the kidney disease? Reports of pregnancy outcomes in women with CKD from the 1950s and 1960s painted a very bleak outlook for mothers and infants; however, the following decades have identified a large population of women who have little, if any, problems. Identification of women at higher risks can facilitate individualization of care and optimize outcomes.

Measuring Renal Function in Pregnancy


Glomerular filtration rate: creatinine is a metabolic by-product of muscle metabolism that is filtered and excreted through the renal tract, and, as

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such, serum creatinine levels are inversely proportionate to GFR. Serum creatinine is also affected by age, ethnicity, medication, diet, gender, and body composition, however, so absolute serum creatinine concentrations correlate poorly with GFR between individuals. In the general population, serum creatinine has been superseded by eGFR as a marker of renal function. eGFR is calculated from serum creatinine, patient age, gender, and ethnicity. Importantly, this calculation is not validated for use during pregnancy and should not be used. Alternatively, renal function during pregnancy can be estimated by creatinine clearance. The utility of calculated creatinine clearance is limited by the requirement for a 24-hour urine collection. This is inconvenient and frequently incomplete. Since the eGFR equation is invalid during pregnancy and creatinine clearance is inconvenient, most centres continue to rely on changes in serum creatinine concentration to identify potential renal dysfunction during pregnancy, mindful that relative changes in creatinine have greater clinical utility than absolute values. Preconception baseline values of eGFR are useful in predicting maternal and fetal outcomes, however (see below). Proteinuria: this is an independent predictor of progressive renal failure in patients with CKD and a diagnostic marker of preeclampsia in pregnancy. Traditionally, protein excretion is quantified by measurement of a 24-hour collection of urine. This is inconvenient for the patient and collections are often incomplete. Nevertheless, if performed correctly, this remains the most accurate method available. In general nephrological practice and obstetric medicine, the protein to creatinine ratio (PCR) or albumin to creatinine ratio (ACR) are accepted as surrogates for 24-hour collections. Assuming steady production and excretion of creatinine, this

method corrects for variations in urine concentration and correlates closely with complete 24-hour urine collection data, including in pregnant patients with CKD. PCR or ACR can be used for quantitative monitoring of proteinuria during pregnancy.

Fetal Outcomes
Adverse fetal outcomes (preterm delivery, small for gestational age, neonatal intensive care admission, persistent congenital disability, or death) occur in 18% of pregnancies in mothers with CKD compared with 9% in those without CKD. Risks can be stratified according to baseline maternal renal function, blood pressure control, proteinuria, and, to a lesser extent, aetiology of renal disease. Renal function: the risks of adverse fetal outcomes increase with the severity of baseline renal dysfunction. Even early CKD (preconception eGFR > 60 mL/min) is associated with increased risk of prematurity and intrauterine growth restriction (IUGR) as compared with the general population, predominantly because of an increased risk of developing pre-eclampsia. Mothers with more severe renal dysfunction (baseline serum creatinine > 180 mmol/L) are faced with risks of IUGR 65%, preterm delivery 90%, and perinatal mortality 10%. Aetiology of CKD: the aetiology of CKD has minimal impact on fetal outcome, with a few exceptions. Asymptomatic bacteriuria and recurrent urinary tract infection (UTI), secondary to vesicoureteric reflux or structural abnormalities, are associated with an increased risk of preterm delivery. Diabetes mellitus and systemic lupus erythematosus (SLE) may cause CKD, but adverse fetal outcomes are also associated with non-renal components of these conditions, such as hyperglycaemia, thrombophilia, and antinuclear antibodies. Hypertension: uncontrolled hypertension in patients with CKD prior to conception or in early pregnancy is a key independent predictor of adJPOG SEP/OCT 2013 197

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Box 1. National High Blood Pressure Education Program Report on High Blood Pressure in Pregnancy criteria for the diagnosis of superimposed pre-eclampsia

sence of preeclampsia, although it remains unclear whether this reflects early induction of labour or spontaneous premature labour. Nephrotic syndrome (proteinuria > 3 g/d, serum albumin < 30 g/L, and oedema) occurs rarely in pregnancy and is almost always a result of pre-eclampsia. Nephrotic syndrome in the first trimester represents intrinsic renal disease and previous case series reported perinatal mortality of > 40%. More recent series suggest that outcomes are much more favourable, however, with mortality < 5% in the UK.

Blood pressure > 160/110 mm Hg Blood control suddenly worsening after a period of good control  Development of proteinuria > 2,000 mg/d or abrupt worsening of proteinuria Serum creatinine increasing to > 110 mmol/L

verse fetal outcome. Blood pressure increases in the second half of pregnancy may be exaggerated in women with CKD owing to limitations in vascular relaxation and increasing circulating volume as a result of relative over-activity of the renin-angiotensin system. Elevated blood pressure at baseline predicts the occurrence prematurity, IUGR, and neonatal mortality. In optimizing fetal outcomes, blood pressure treatment targets for women with CKD are controversial. Fetal outcomes are similar in those with mild to moderate high blood pressure (< 160/100 mm Hg) and in patients treated for hypertension. Aggressive treatment of maternal hypertension during pregnancy (< 120/80 mm Hg) may lead to IUGR. In the absence of high-quality evidence, consensus guidelines from the Royal College of Obstetricians and Gynaecologists (RCOG) state that in patients with CKD, it is recommended to target a blood pressure of < 140/90 mm Hg, predominantly to reduce maternal complications (see below). Proteinuria: elevated urine protein excretion is associated with IUGR and preterm delivery. In women without CKD, this effect can be almost wholly accounted for by concurrent co-morbidity (predominantly hypertension, diabetes mellitus, or pre-eclampsia). In women with CKD, however, increased proteinuria (> 1 g/d) at baseline is associated with early delivery and small infants in the abJPOG SEP/OCT 2013 198

Maternal Outcomes
Adverse maternal outcomes for women with CKD include preeclampsia, transient decline in renal function, persistent loss of renal function, requirement dialysis, and death. As with fetal outcomes, risks can be stratified according to baseline maternal renal function, blood pressure control, proteinuria, and aetiology of renal disease. Pre-eclampsia: the risk of developing preeclampsia for mothers with CKD is greatly increased compared with the general population, and increases with worsening renal function: 20% for patients with mild renal dysfunction (serum creatinine < 125 mol/L) and 6080% with severe impairment (serum creatinine > 180 mol/L), compared with approximately 5% in the general population. These estimations vary between studies as a result of heterogeneity between study cohorts and variations in diagnostic criteria used. CKD is commonly associated with proteinuria and hypertension prior to conception, and the diagnosis of superimposed pre-eclampsia relies on arbitrary increases in these parameters with or without additional clinical features of pre-eclampsia (Box 1). Renal function: decline in renal function during pregnancy occurs rarely in patients with mild renal impairment at baseline (serum creatinine < 125 mol/L) and often reflects an episode of ob-

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struction, pyelonephritis, or pre-eclampsia. In such cases, return to baseline renal function almost always occurs within 3 months post partum. In contrast, women with moderate CKD (serum creatinine > 125 mol/L) have a 25% risk of permanently losing 25% of their kidney function as a result of pregnancy, increasing to a 50% risk in those with baseline creatinine > 180 mol/L. Furthermore, women with a preconception serum creatinine > 180 mol/L have a one in three chance of requiring dialysis during pregnancy or within 6 months of delivery. Aetiology of CKD: the underlying aetiology of CKD has little impact on maternal outcome independent of renal function and blood pressure control. There is an increased risk of asymptomatic bacteriuria progressing to overt infection and pyelonephritis during pregnancy. Patients with recurrent UTI or vesicoureteric reflux are at particular risk and should be screened for bacteriuria by dipstick analysis and urine culture. Asymptomatic bacteriuria should be actively treated to reduce the risk of potentially serious sepsis and reduce the incidence of preterm delivery. Lupus nephritis often enters a phase of quiescence during pregnancy as a result of increased endogenous corticosteroid production. Consequently, flares can often occur in the puerperium when increased vigilance is recommended. If lupus flares do occur during pregnancy, they can be difficult to distinguish from pre-eclampsia hypertension, proteinuria and decline in renal function, often with thrombocytopenia. The presence of invisible haematuria, depressed serum complement levels, a rise in anti-double-stranded DNA titre, and cutaneous manifestations of SLE support a diagnosis of a lupus flare and should be treated promptly. Renal biopsy may be required if renal function declines quickly, or if nephrotic syndrome develops, in order

to determine the most appropriate treatment for the renal disease. Patients with SLE and antiphospholipid antibodies are at greatly increased risk of thromboembolic disease and pre-eclampsia. Hypertension: chronic hypertension is common in patients with CKD. Control may become more difficult during pregnancy owing to cardiovascular adaptations in the second and third trimesters and the unsuitability of some antihypertensives during pregnancy, even in the absence of pre-eclampsia. Most notably, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are commonly prescribed for patients with proteinuric CKD owing to their effectiveness and renoprotective properties; however, they are associated with severe congenital abnormalities and should be avoided during pregnancy (see below). There are contradictory reports of the impact of blood pressure during pregnancy on progression of maternal renal disease; however, contemporary prospective data suggest that baseline diastolic blood pressure > 75 mm Hg or use of antihypertensive agents is predictive of accelerated decline in renal function post partum. Severe hypertension (> 160/100 mm Hg) in the third trimester requires treatment to reduce the risk of intracerebral haemorrhage in labour. Proteinuria: increased urine protein excretion is predictive of progressive renal dysfunction in general nephrology where proteinuria per se is believed to be nephrotoxic. During normal pregnancy, where urinary protein excretion can double, the impact of proteinuria on kidney function is less clear, certainly in the short to medium term. In patients with eGFR < 40 mL/min before conception, proteinuria > 1 g/d is associated with an increased rate of renal decline post partum compared with those with less proteinuria. No similar effect was seen in patients with preserved renal function.
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Mothers who develop nephrotic syndrome during pregnancy are at increased risk of venous thromboembolism. Loss of antithrombotic serum components in the urine leads to increased thrombotic tendency, and strong consideration should be given to the use of prophylactic anticoagulation with low-molecular-weight heparin (LMWH) (see below). In the absence of nephrotic syndrome or renal dysfunction, proteinuria does not appear to have a prominent independent effect on maternal outcomes during pregnancy; however, there is emerging evidence that baseline proteinuria may predict the risk of loss of renal function or dialysis post partum.

lection should be performed early in pregnancy to determine baseline renal function and urine protein excretion. Patients should have the following recorded at every subsequent visit: blood pressure urine dipstick  urine PCR or ACR, and/or urine culture, if dipstick positive Depending on the level of renal function at baseline, the following should be measured every 68 weeks during pregnancy: serum creatinine and urea haemoglobin More frequent measurement is required if renal function is abnormal or deteriorating. Serum ferritin, folate, and vitamin B12 should be measured if anaemia is identified; serum albumin, calcium, and vitamin D are indicated in women with heavy proteinuria (PCR > 100 mg/mmol) or advanced renal dysfunction (creatinine > 180 mol/L). Women with a history of recurrent UTI or structural abnormalities should submit a urine sample for culture every month irrespective of symptoms to identify asymptomatic bacteriuria. A renal ultrasound is required during pregnancy if there is a sudden decline in renal function there are signs or symptoms suggestive of ob  struction or renal stone disease As above, mild pelvicalyceal dilatation is commonly identified during normal pregnancy. Functional ureteric obstruction should only be suspected if there is progressive dilatation on serial renal ultrasound scans, suggestive signs and symptoms or obstruction, or worsening renal function. Investigations suspected new diagnosis of CKD: renal disease might be discovered during pregnancy and should be suspected in women with hypertension, proteinuria, or haematuria identified

Management
Preconception counselling: ideally, all patients with CKD should be offered counselling prior to conception in order to evaluate the risks of proceeding with pregnancy and the likely outcomes. Medications known to be harmful to the developing fetus can be discontinued or substituted for safer alternatives (see Tables 3 and 4 below). Patients with active lupus nephritis or vasculitis and those with poorly controlled blood pressure should be advised to wait until these are optimized before trying to conceive. Similarly, patients with significant renal dysfunction (serum creatinine > 180 mol/L) may not accept the risks associated with proceeding with pregnancy and may be better advised to wait until they have received a renal transplant (see below). In the majority of cases, patients need not be discouraged from trying to conceive as long as the potential risks are understood and the pregnancy is closely monitored. Investigations pre-existing CKD: if preconception results are unavailable, serum creatinine and either urine PCR/ACR or 24-hour urine colJPOG SEP/OCT 2013 200

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at booking or in early pregnancy. A renal ultrasound is helpful to characterize the aetiology and chronicity of CKD. Large kidneys on ultrasound may reflect polycystic kidney disease, diabetic nephropathy, or chronic obstruction. Focal scarring of kidneys may reflect a congenital abnormality of the kidney and urinary tract in the mother, most commonly vesicoureteric reflux. Small kidneys may be the result of any chronic process, and further diagnosis may be difficult. Immunological investigations should be requested if there is suspicion of intrinsic renal disease haematuria, proteinuria, decreased renal function, and/or hypertension (Table 2). Aetiology of intrinsic renal disease may be confirmed by renal biopsy and can be performed during pregnancy, but should be reserved for unexplained decline in kidney function in CKD  or acute kidney injury newly diagnosed nephrotic syndrome  features suggestive of systemic disease or vasculitis A renal biopsy is not indicated to investigate stable CKD, non-nephrotic range proteinuria, or pre-eclampsia, and not after 32 weeks gestation when the pregnancy should be brought to an end prior to renal investigation. Blood pressure control (Tables 3 and 4): methyldopa, labetalol, nifedipine, and hydralazine are the most frequently used agents to treat hypertension in pregnancy. All appear to be safe and well tolerated in pregnancy. Methyldopa should be avoided in patients with depression. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be avoided throughout pregnancy as they are associated with congenital malformations and fetal urinary tract agenesis. Women for whom there is a strong indication for these agents (heavy proteinuria, diabetic nephropathy, or heart disease) may be advised to

Table 2. Immunological investigation of suspected intrinsic renal disease

Test Anti-nuclear antibodies (ANA)

Comments Associated with connective tissue diseases and SLE. Antibodies against double-stranded DNA (anti-dsDNA) and extractable nuclear antigens (ENA) should be performed if positive Associated with small vessel vasculitis (Churg-Strauss disease, granulomatosis with polyangiitis, and microscopic polyangiitis) Decreased levels are found in active SLE, post-infectious glomerulonephritis, mesangiocapillary glomerulonephritis, subacute bacterial endocarditis, cryoglobulinaemia, and heavy chain-deposition disease Rheumatoid factor, cryoglobulins, and C3 nephritic factor measurement may be indicated

Anti-neutrophil cytoplasmic antibodies (ANCA)

Complement components C3 and C4

Other tests

SLE = systemic lupus erythematosus.

continue therapy until conception is confirmed, but a discussion regarding the potential risks should be held as part of preconception counselling. Labetalol appears safe, but other beta-blockers have been associated with IUGR. Diuretics can exacerbate intravascular volume depletion in hypertensive disorders of pregnancy and lead to IUGR. For patients with CKD, it is well recognized that control of hypertension is essential to abrogate decline in renal function. Consensus guidelines derived from the RCOG Study Group on renal disease and pregnancy recommend that a target blood pressure of 140/90 mm Hg is maintained during pregnancy. Data to support blood pressure treatment targets for patients with CKD during pregnancy are lacking, however.
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Table 3. Medications used in chronic kidney disease and pregnancy

evidence to support prophylaxis for women with heavy proteinuria but no nephrotic syndrome, or more modest proteinuria. Nevertheless, many practitioners encourage the use of LMWH throughout pregnancy for women with a PCR > 100 mg/mmol, particularly if women are obese or have other risk factors for venous thromboembolism. Advice on thromboprophylaxis in pregnancy is published by the RCOG. LMWH should be continued for at least 6 weeks following delivery. UTI prophylaxis (Tables 3 and 4): confirmed asymptomatic bacteriuria and symptomatic UTI during pregnancy should be treated with antibiotics to reduce the risk of ascending infection and preterm delivery. If more than one episode of bacteriuria is confirmed during pregnancy, prophylactic antibiotics should be prescribed. The choice of antibiotic is determined by stage of pregnancy, sensitivities of the cultured organisms, and local practice. Cephalosporins and penicillins are safe and well tolerated throughout pregnancy. Gentamicin may be used for severe pyelonephritis with appropriate monitoring. Trimethoprim is a folate antagonist and should be avoided in the first trimester. Nitrofurantoin is as-

Commonly used Nifedipine Labetalol Methyldopa Hydralazine

Rarely used Antihypertensives Beta-blockers Alpha-blockers Amlodipine Verapamil

Contraindicated ACE inhibitors Angiotensin receptor blockers Aliskiren Spironolactone Moxonidine Minoxidil (3rd trimester) Thiazide diuretics Diltiazem

Likely to be safe Prednisolone Azathioprine Ciclosporin Tacrolimus

Likely to be harmful Contraindicated Immunosuppressants Anti-thymocyte globulin Rituximab Mycophenolate Sirolimus Methotrexate

ACE = angiotensin-converting enzyme.

Pre-eclampsia prophylaxis: CKD is identified as a high-risk group for developing preeclampsia by the National Institute for Health and Clinical Excellence. Published data support the increased incidence of the condition from severe to mild CKD. In high-risk patients, aspirin (75 mg/d) reduces the incidence of pre-eclampsia by approximately 25%. Although not licenced for this indication, it is recommended that aspirin prophylaxis is offered to all women with CKD during pregnancy. Venous thromboembolism prophylaxis: pregnancy is a prothrombotic state, and this is exacerbated by heavy proteinuria. Consensus opinion recommends that patients with nephrotic syndrome should receive prophylactic LMWH during pregnancy and until 6 weeks post partum. There is less
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sociated with neonatal haemolysis if used in the third trimester and should be avoided. Quinolones should not be used throughout pregnancy. Other medication (Tables 3 and 4): antirejection medications used in renal transplantation are discussed below. Erythropoietin, vitamin D analogues, and intravenous iron appear safe in pregnancy.

DIALYSIS AND PREGNANCY


End-stage renal failure reduces maternal fertility, and conception is rare in patients receiving dialysis. It is estimated that an average-sized renal unit in the United Kingdom will see one case of dialysis and pregnancy per 4 years.

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Approximately 25% of pregnancies in patients on dialysis end with spontaneous abortion or termination in the first trimester. Of those that progress to later pregnancy, adverse events are common: IUGR in 90% preterm delivery in 90% pre-eclampsia in 75% perinatal death in 50%

Table 4. Medications used in chronic kidney disease and breastfeeding

Likely to be safe Hydralazine Nifedipine Methyldopa Most beta-blockers Enalapril Furosemide Thiazide diuretics Minoxidil

Likely to be harmful Antihypertensives Most dihydropyridine calcium channel blockers Celiprolol, nebivolol Alpha-blockers Moxonidine Spironolactone Immunosuppressants

Contraindicated Aliskiren Most ACE inhibitors Angiotensin receptor blockers

Haemodialysis and Pregnancy (Table 5)


The efficiency of haemodialysis (HD) in removing toxic metabolites is affected by the duration of dialysis session, the frequency of dialysis, the surface area of semipermeable membrane, and the blood flow rate. As it is an intermittent process, fluid and circulating uraemic toxins accumulate between treatments. Standard HD schedules are 4-hour sessions three times per week. Observational data suggest that dialysis duration and frequency should be increased during pregnancy to reduce the accumulation of uraemic toxins and interdialytic fluid accumulation between sessions. Dialysis times should be increased to at least 20 hours a week during pregnancy to achieve pre-dialysis urea < 20 mol/L (ideally < 15  mol/L) intradialytic fluid loss of < 1,000 mL per ses  sion Much improved maternal and fetal outcomes have been described in women undergoing nocturnal daily HD five to seven times a week. This is feasible for patients on HD at home but might not be practical for patients dialyzing in units.

Prednisolone Azathioprine

Mycophenolate Ciclosporin Tacrolimus Anti-thymocyte globlin

Sirolimus Rituximab Methotrexate

ACE = angiotensin-converting enzyme.

Table 5. Indications for initiation of renal replacement therapy during pregnancy

Absolute indications Refractory hyperkalaemia Refractory fluid overload Refractory metabolic acidosis Severe uraemia causing encephalopathy or pericarditis

Relative indications Moderate uraemia (urea > 25 mmol/L) Resistant hypertension

Peritoneal Dialysis and Pregnancy


Successful pregnancies can proceed in patients using peritoneal dialysis (PD), although there is limited clinical experience worldwide. The continuous nature of the process limits uraemia and avoids rapid fluid shifts. As pregnancy progresses, the gravid uterus can reduce peritoneal blood flow and prevent instillation of sufficient fluid to make PD effective. In the absence of residual renal function,
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Practice points

blood pressure > 80 mm Hg. Lower blood pressure may contribute to IUGR. Later in pregnancy, blood pressure may rise owing to pre-eclampsia, necessitating further changes in medication. Blood pressure in patients receiving dialysis is predominantly driven by fluid status. A patients dry weight is an estimation of their weight when euvolaemic. During pregnancy, dry weight will increase by approximately 1.5 kg in the first trimester and then 0.5 kg per week until delivery. These changes should be supervised by careful clinical evaluation of the patients fluid status. Anaemia is likely to be accentuated during pregnancy as a result of haemodilution and increased anabolic demand. Erythropoietin replacement during pregnancy appears safe. Required doses may increase by up to three-fold, and intrapatients on PD may be unable to control fluid status adequately during pregnancy, necessitating transfer to HD. Nevertheless, an elective change from PD to HD is not mandatory for patients who are already established on PD at the time of conception. venous iron is usually required to maintain stores. A target haemoglobin of 1011 g/dL has been suggested.

 Maternal and fetal risks are proportional to renal function and blood pressure control prior to conception  Women with chronic kidney disease should be offered aspirin prophylaxis during pregnancy to reduce the risk of pre-eclampsia  Women with heavy proteinuria are at increased risk of thromboembolism and should be considered for prophylaxis during pregnancy  Asymptomatic bacteriuria and urinary tract infection should be promptly treated during pregnancy  Optimizing timing of delivery requires multidisciplinary input from nephrologists, neonatologists, obstetricians, and patients

KIDNEY TRANSPLANTATION AND PREGNANCY


The first successful pregnancy in a recipient of a kidney transplant occurred in March 1958. Over 15,000 children have been born to mothers with renal transplants since then. Maternal and fetal outcomes for pregnancies following renal transplantation are far superior to those for mothers on dialysis. The risks are predominantly related to the level of renal function at conception and blood pressure control. Transplant rejection and function are not affected by pregnancy assuming the following are met: at least 12 months post transplant stable renal function proteinuria < 1 g/d minimal or well-controlled hypertension no recent or ongoing transplant rejection

Pre-eclampsia and Dialysis


Pre-eclampsia is common, can occur early, and may be severe. The diagnosis of pre-eclampsia is made in the context of worsening hypertension with additional clinical features such as coagulopathy, liver dysfunction, IUGR, or neurological symptoms. Dialysis patients usually display urinary dipstick abnormalities or may be anuric, so testing for proteinuria is unhelpful.

Management on Dialysis
Intensive dialysis and fluid removal can accentuate the haemodynamic changes in pregnancy, causing blood pressure instability and hypotension. However, many dialysis patients have treated chronic hypertension prior to conception, and medication may need to be reduced to maintain a diastolic
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 minimal levels of appropriate immunosuppression (see below) For mothers with baseline creatinine < 125 mol/L, successful pregnancy occurs in 97% of cases reaching the second trimester. The incidence of preterm delivery, IUGR, and pre-eclampsia is greater than the general population, and 30% of pregnancies may be affected. With more severe baseline renal dysfunction, the incidence of adverse fetal outcome increases. The likelihood of accelerated maternal renal decline is also higher. In one study, all transplant patients with creatinine > 200 mol/L at conception progressed to dialysis within 2 years. There is no evidence of delayed development in children born to mothers with a renal transplant, independent of complications associated with preterm delivery. Normal vaginal delivery is not contraindicated following renal transplantation. If caesarean section is indicated, then a lower segment approach may be difficult owing to the course of the transplanted ureter. In transplantation, a combination of prednisolone, azathioprine, and tacrolimus or cyclosporine can be used during pregnancy (see Table 3). Although there is many decades experience of use of these agents during pregnancy, women should be informed of the recognized patterns of reported side effects: at high doses (> 20 mg/d) prednisolone can  lead to fetal adrenal insufficiency and risk of maternal infection. Maintenance doses of < 10 mg/d appear safe and well-tolerated in pregnancy cyclosporine and tacrolimus may exacerbate  hypertension and limit renal adaptation to pregnancy. Fetal growth restriction may be associated with these agents  azathioprine is teratogenic in high doses in

animal studies. In humans, it has been used without obvious teratogenicity. It may be associated with fetal growth restriction Trough serum levels of the calcineurin inhibitors tacrolimus or cyclosporine should be measured at every visit. Altered pharmacodynamics during pregnancy necessitates careful titration of doses of these drugs to maintain adequate levels whilst avoiding toxicity. A dose increase of up to four-fold may be required, and close monitoring in the puerperium is as important as during pregnancy, if not more so. Mycophenolate mofetil (and mycophenolic acid) is commonly prescribed following renal transplantation but should be avoided during pregnancy owing to a high incidence of specific congenital abnormalities being reported. Patients should also be switched from sirolimus prior to conception.

FURTHER READING
Davison JM, Nelson-Piercy C, Kehoe S, Baker P, eds. Renal disease in pregnancy. London: RCOG Press, 2008. Gammill HS, Jeyabalan A. Acute renal failure in pregnancy. Crit Care Med 2005;33:S372 S384. McKay DB, Josephson MA. Pregnancy in recipients of solid organs effects on mother and child. N Engl J Med 2006;354:12811293. Williams D, Davison J. Chronic kidney disease in pregnancy. BMJ 2008;336:211215.

2012 Elsevier Ltd. Initially published in Obstetrics, Gynaecology And Reproductive Medicine 2012;23(2):3137.

About the Authors


Matt Hall is a Consultant in Renal Medicine at Nottingham Transplant and Renal Unit, Nottingham City Hospital, Nottingham, UK. Nigel J Brunskill is Professor of Renal Medicine at the John Walls Renal Unit, Leicester General Hospital, Leicester, UK.

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Dermatology Clinic
Sudden Onset of Blistering Lesions in a Young Boy
Gayle Fischer, MB BS, MD, FACD

CASE HISTORY
A 12-year-old boy presents with sudden onset of blistering lesions on his arms and legs (Figure 1), occurring a few days after he developed a typical cold sore on his upper lip.

What is the most likely diagnosis of these blistering lesions?


(Answers on p. 211)

Figure 1. Blistering lesions on the patients arm (a, top) and leg (b, bottom).

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Carbetocin in the Prevention of Perinatal Case Management Postpartum Haemorrhage: Caring for Mothers as They Care An Asian Perspective for Babies
Shilla Mariah Yussof, MB BCh BAO (Hons) (Dublin); Horng Yen Wee, MB BCh BAO (Dublin), BA (Dublin), FAMS (Singapore), MRCOG (UK) Chng Ying Chia, MA (Applied Social Studies); Jemie Biwen Wang, Bachelor of Psychology (Hons); Helen Chen, MBBS, M Med (Psych), Dip. Psychotherapy

INTRODUCTION
Postpartum haemorrhage (PPH) is one of the leading causes of maternal morbidity and mortality. While the rate of PPH varies widely among different countries, it accounts for approximately 30% of maternal deaths in Asia. 1 The prevalence of PPH in South-eastern Asia was estimated to be 4.88%, the highest within Asia, which has an average PPH rate of 2.55%.2 The main cause of PPH is uterine atony. Active management of the third stage of labour, which consists of early cord clamping, controlled cord traction, and the prophylactic administration of a uterotonic agent, has been widely used worldwide to reduce PPH. Of these measures, uterotonic agent is the only one supported by extensive evidence.3 The World Health Organization currently recommends active management of the
4 third stage of labour with oxytocin to prevent PPH. However, the half-life of this drug is

rather short (410 minutes), and it has to be administered continuously via intravenous infusion to achieve sustained uterotonic activity.57 Its dose and duration vary widely across institutions.811 Another widely used uterotonic agent is syntometrine, a derivative of oxytocin and ergometrine. It is superior to oxytocin in risk reduction of mild PPH (5001,000 mL).12 However, syntometrine is limited by its gastrointestinal and cardiovascular side effects, which include maternal vomiting, hypertension, and pain requiring analgesia owing to its ergot alkaloid component. 13 The use of ergot alkaloids is also contraindicated in women with pre-existing hypertension, pre-eclampsia, and cardiac conditions, and in those with a history of migraine or Raynaud phenomenon. Ergometrine is also very unstable and has to be kept refrigerated and shielded from light, which limits its use in rural areas.
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CARBETOCIN PHARMACOLOGIC PROPERTIES


Carbetocin is an oxytocin agonist. With pharmacologic properties similar to natural oxytocin, the drug binds to the smooth muscle receptors of the uterus, causing rhythmic contractions and increasing the frequency of contractions as well as uterine tone.
14,15

nausea, vomiting, and hypertension after delivery.

18

Another study by Ngan et al in Macau compared 100 g carbetocin and a combination of 5 IU of oxytocin and 0.2 mg of ergometrine in the control of postpartum blood loss in 118 women following vaginal delivery.19 They found that carbetocin was associated with significantly less blood loss (mean, 163 mL less) and haematocrit drop, and a statistically significant reduction in the risk of PPH.19 Nirmala et al in Malaysia compared the use of carbetocin and syntometrine following vaginal delivery in 120 women with risk factors for PPH. 20 No significant differences in terms of requirement for additional oxytocic agents, time interval to wellcontracted uterus, blood transfusion requirements, adverse events, or complications were noted.
20

Administered either intravenously or in-

tramuscularly as a single dose of 100 g, carbetocin has a half-life of about 40 minutes; 410 times longer than that of oxytocin. 16 Contraction of the uterus can be achieved within 2 minutes following injection, persisting for an average of 120 minutes following intramuscular injection and an average of 60 minutes with intravenous injection.
17

The main

advantage of carbetocin over oxytocin is its longer duration of action, allowing a single intramuscular injection instead of an intravenous infusion. As such, carbetocin is a promising alternative uterotonic agent for the prevention of PPH.

Carbetocin, however, was associated with a significantly lower mean estimated blood loss. 20 The haemoglobin showed a significantly reduced drop in the carbetocin group compared with that in the syntometrine group.20 Su et al in Singapore conducted a doubleblind, randomized, controlled trial of 370 women comparing the use of carbetocin and syntometrine for the third stage of labour following vaginal delivery.21 Carbetocin was shown to be as effective as syntometrine in the prevention of PPH but had fewer adverse events. 21 Women given syntometrine were four times more likely to experience nausea and vomiting compared with those who had carbetocin. Tremor, sweating, retching, and uterine pain were also more likely in the syntometrine group compared with the carbetocin group.
21

CARBETOCIN IN VAGINAL DELIVERIES


A number of studies have evaluated the efficacy of carbetocin in vaginal deliveries. Asian data from a study by Leung et al in Hong Kong compared carbetocin and syntometrine in the management of the third stage of labour in 300 women undergoing vaginal delivery. The authors found that intramuscular carbetocin was as effective as intramuscular syntometrine in preventing primary PPH but was less likely to induce hypertension after delivery.
18 18

There was no difference in the drop of haemoglobin concentration within the first 48 hours between the two groups. 18 The incidence of additional oxytocic injections, PPH, and retained placenta were also similar.
18

CARBETOCIN IN CAESAREAN SECTIONS


There are currently no Asian studies evaluating the efficacy and safety of carbetocin in caesarean sections. Nevertheless, according to a recent Cochrane

However, the use of carbetocin was

associated with a significantly lower incidence of


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Table 1. Summary of oxytocic drugs currently available26-28

pared the adverse effects of different uterotonic agents.22 The risk of experiencing headache, chills, abdominal pain, dizziness, tremor, nausea, vomiting, back pain, pruritus, feeling of warmth, metallic taste, flushing, sweating, shortness of breath, and premature ventricular contractions were similar between the carbetocin and oxytocin groups for both vaginal and caesarean deliveries. Although women who underwent vaginal deliveries experienced fewer headaches, nausea, and vomiting when treated with carbetocin compared with oxytocin, the difference was not statistically significant. When compared with syntometrine in vaginal delivery, the risk of nausea (RR, 0.24; 95% CI, 0.150.40) and vomiting (RR, 0.21; 95% CI, 0.110.39) was significantly lower in the women treated with carbetocin.
22

Carbetocin (Duratocin) Active Carbetocin ingredient 100 g in 1-mL ampoule Dosage IV bolus: 100 g Within 2 min

Oxytocin (Syntocinon) Oxytocin 5 IU or 10 IU in 1-mL ampoule IV infusion: 5 IU IM: 510 IU IV: < 1 min IM: 24 min IV: less than IM IM: 3060 min Headache, hypotension, tachycardia/ bradycardia

Oxytocin/ergometrine (Syntometrine) Oxytocin 5 IU + 0.5 mg ergometrine maleate in 1-mL ampoule IM: maximum three ampoules within 24 h (interval of 2 h) ~2.5 min ~3 h Nausea and vomiting, hypertension, cardiac arrhythmias

Onset of action

Duration of ~1 h action Adverse reaction Nausea and vomiting, abdominal pain, hypotension

Women who received carbetocin were also less likely to have hypertension at 30 minutes (RR, 0.07; 95% CI, 0.010.49; two trials, 570 women) and at 60 minutes (RR, 0.07; 95% CI, 0.010.54; two trials, 540 women) after vaginal delivery.22 See Table 1 for a summary of oxytocic drugs currently available.

IM = intramuscular; IV = intravenous.

review, the risk of PPH in caesarean deliveries was similar in women treated with carbetocin and oxytocin (relative risk [RR], 0.91; 95% CI, 0.392.15;
22

COST-EFFECTIVENESS OF two trials, 432 women). In addition, compared CARBETOCIN


with the oxytocin group, the need for subsequent additional uterotonics was lower in the carbetocin group (RR, 0.62; 95% CI, 0.440.88; four trials, 1,173 women). There was no statistically significant difference in the need for blood transfusion between the carbetocin and syntometrine group. Similar to vaginal deliveries, there was also a reduced need for uterine massage when comparing carbetocin and oxytocin (RR, 0.54; 95% CI, 0.370.79; two trials, 739 women).
22 22 22

Many factors, such as cultural differences, government policy, availability of trained medical staff, storage space, and cost-effectiveness, may contribute to differences in the management of PPH and, ultimately, the choice of uterotonic agents. Although there is currently limited data on the costeffectiveness of individual uterotonic agents, one study from Mexico compared the cost-effectiveness of prophylactic carbetocin with oxytocin following caesarean delivery. 23 The authors compared the incidence of uterine atony in patients receiving carbetocin vs oxytocin (8% vs 19%; P < 0.0001) and, with additional financial data from the Mexican Institute of Social Security, were able to calculate
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CARBETOCIN SAFETY AND TOLERABILITY


The recent Cochrane review by Su et al also com-

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the mean cost-effectiveness ratio using incremental cost-effectiveness ratio analysis.


23

worldwide. Prophylactic administration of a uterotonic agent plays an important role in the prevention of PPH. While there are already numerous effective agents available on the market, each agent has its own advantages and drawbacks. While both oxytocin and ergometrine are effective in preventing PPH, oxytocin is limited by its short duration of action, whereas syntometrine is associated with multiple side effects. Carbetocin is a long-acting oxytocin analogue that combines the safety and tolerability of oxytocin with sustained uterotonic activity. So far, data from several studies, including meta-analyses, have shown that carbetocin is effective and safe in both caesarean and vaginal delivery, with a better side effect profile. These promising findings suggest that carbetocin may be suitable as the drug of choice for primary prevention of PPH. Further studies on the cost effectiveness of carbetocin, compared with other uterotonic agents, and the use of carbetocin as a therapeutic agent for PPH are useful areas to be explored.

The mean cost

per patient treated was lower for the carbetocin group (US$3,525 vs US$4,054; P < 0.0001), suggesting that carbetocin was more cost-effective.
23

CURRENT USE OF CARBETOCIN


Carbetocin has been approved for use in the prevention of uterine atony after delivery by caesarean section with spinal or epidural anaesthesia in 23 countries, including China, Hong Kong, Malaysia, and Singapore. The Royal College of Obstetricians and Gynaecologists states that carbetocin is as effective as oxytocin infusion for the prevention of PPH in caesarean section and syntometrine in vaginal delivery.
24

However, the drug is currently not

recommended for routine use owing to the limited data to support its cost-effectiveness. The Society of Obstetricians and Gynaecologists of Canada recommends the use of carbetocin for the prevention of PPH instead of continuous oxytocin infusion in elective caesarean section and for women delivering vaginally with one risk factor for PPH.25

About the Authors


Dr Yussof is Medical Officer in the Department of Obstetrics and Gynaecology at KK Womens and Childrens Hospital. Dr Wee is Senior Consultant, and Obstetrician and Gynaecologist at Novena Medical Centre; and Visiting Consultant in the Department of Obstetrics and Gynaecology at KK Womens and Childrens Hospital, Singapore.

CONCLUSION
Postpartum haemorrhage is one of the most common causes of maternal morbidity and mortality Acknowledgement

This paper was made possible through a collaboration between KK Womens and Childrens Hospital (KKH) and the Journal of Paediatrics, Obstetrics and Gynaecology. KKH is the largest medical facility in Singapore which provides specialized care for women, babies and children.

REFERENCES
1. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PFA. WHO analysis of causes of maternal death: a systematic review. Lancet 2006;367:10661074. 2. Carroli G, Cuesta C, Abalos E, Gulmezoglu AM. Epidemiology of postpartum haemorrhage: a systematic review. Best Pract Res Clin Obstet Gynaecol 2008;22:9991012. 3. Aaifel N, Weeks AD. Active management of the third stage of labour. BMJ 2012;345:e4546. 4. World Health Organization. WHO guidelines for the management of postpartum haemorrhage and retained placenta. Availableat:http://whqlibdoc.who.int/publications /20 09/9789241598514_eng.pdf.Accessed November 23, 2012. 5. Ryden G, Sjoholm I. Half-life of oxytocin in blood of pregnant and non-pregnant women. Acta Endocrinol (Copenh) 1969;61:425431. 6. Fabian M, Forsling M, Jones J. The clearance and antidiuretic potency of neurohypophysial hormones in man, and their plasma binding and stability. J Physiol 1969;204:653668.

A complete list of references can be obtained upon request to the editor.

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Dermatology Clinic
Sudden Onset of Blistering Lesions in a Young Boy
Gayle Fischer, MBBS, MD, FACD

Answer: ure 2, but careful observation reveals that spectrum ranging from a benign blistering rash involving only the arms and legs to a widespread life-threatening erup-

ERYTHEMA MULTIFORME

these lesions are in fact simply annular. Differentiating erythema multiforme from

DIAGNOSIS AND DIFFERENTIAL urticaria is straightforward. The lesions in tion causing severe erosions of all muurticaria never blister and always migrate cosal surface including the conjunctivae. DIAGNOSIS
if observed over several hours. Erythema The diagnosis in this case is erythema multiforme. Careful observation of these blisters show that they have the morphology of target lesions. Although not every lesion demonstrates this, most have a red areola, then an area of grey with a red centre. True target lesions are highly characteristic of erythema multiforme. multiforme lesions are fixed and last up to 2 weeks. However, both conditions are often acute in onset. Other causes of blistering rashes include bullous impetigo, other viral exanthemata, and tinea. Many cases of erythema multiforme are the result of a recent herpes simplex infection such as a cold sore; however, infections with Mycoplasma pneumoniae may also result in severe erythema multiforme. Less often, drug eruptions may result in the same type of rash. When caused by herpes simplex infection, erythema multiforme often recurs with each attack. This can be highly disruptive as the rash lasts for about 2 Erythema multiforme has a wide clinical weeks.

CLINICAL SPECTRUM AND The most common condition confused CAUSES

with erythema multiforme is urticaria, which may be targetoid, as shown in Fig-

Figure 2. Targetoid urticaria


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IN PRACTICE I In nP Practice ractice I I PEER PEER REViEWED REVIEWED

Figure 3. Severe mucosal erosions of erythema multiforme.

CONFIRMING THE DIAGNOSIS


Erythema multiforme has a very characteristic skin biopsy appearance. Histology will also rule out other causes of blistering eruptions. Blistering lesions should be swabbed for bacterial culture. Once the diagnosis is established, all new medications should be stopped and antibody titres for mycoplasma requested. It is often difficult to prove a recent herpes simplex infection, as these can be subclinical, serology can be unreliable, and there may be no obvious lesion from which to take a sample for viral culture. However, because herpes simplex is such a common cause, it is not unreasonable to assume such infection is responsible until proven otherwise.
JPOG SEP/OCT 2013 212

MANAGEMENT
In mild cases, particularly when there has been a clear history of a recent herpes simplex infection, patients should be given oral antiviral medication and, to mitigate the severity of the attack, oral prednisone. If the patient is unwell and has severe mucosal involvement, he or she should be admitted to hospital and commenced on intravenous aciclovir and a macrolide antibiotic to cover the possibility of mycoplasma infection until titres are available. In these severe cases, the literature suggests that prednisone is unhelpful; however, supportive care of the patient needs to be maximal and multidisciplinary, often necessitating admission to a high dependency or intensive care unit.

PROGNOSIS
With good care, patients have an excellent prognosis; but in those with recurrent disease due to herpes simplex virus infection, long-term oral antiviral prophylaxis is required.

2013 Medicine Today Pty Ltd. Initially published in Medicine Today June 2013;14(6):6061. Reprinted with permission

About the Author


Associate Professor Fischer is Associate Professor of Dermatology at Sydney Medical School Northern, University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia.

Continuing Medical Education


P 5 SK

Screening for Group B Streptococcus in Pregnancy


KY Leung, MBBS, MD, FRCOG, FHKAM(O&G); Teresa WL Ma, MBBS, FRCOG, FHKAM (O&G); KKW To, MBBS, MRCP, FRCPath, FHKAM (Pathology); KY Wong, MBBS, MRCP, FHKAM (Paediatrics); Thomas KT Li, MBChB(HK), DRCOG, MRCOG, DCG(HKCOG), FHKAM(O&G); CW Law, MBBS, MRCP, FHKCPaed, FHKAM (Paediatrics); Sarah Morag McGhee, BA, BSc, PhD Glas, FFPH (RCP) UK

in the Centers for Disease Control and

search has focused on the improvement of microbiological techniques to detect GBS colonization and infection. The aim of this review article is to discuss the current screening methods for GBS in pregnancy, the updated CDC guidelines, the improvement in laboratory techniques, and a pilot study in Hong Kong.

INTRODUCTION
Group B Streptococcus (GBS) is the commonest cause of severe early-onset neonatal infection, which is associated with a high rate of morbidity and mortality (510%).
13

Prevention (CDC) guidelines in 2002 and 2010. Because of the lack of local data,
7

a 1-year pilot study on universal prenatal swab-based screening was conducted in a public hospital in Hong Kong to study the cost-effectiveness. The conventional laboratory test for GBS is culture. Recent re-

About half of GBS meningitis

will be complicated by neurodevelopment impairment. Because the early-onset disease develops shortly and rapidly after birth, there has been little improvement in the disease treatment, and the focus thus lies in disease prevention. GBS colonization in the maternal gastrointestinal and/or genital tracts is a prerequisite for early-onset GBS (EOGBS) disease. It is well documented that intrapartum antibiotics prophylaxis (IAP) given to high-risk women can reduce the GBS colonization rate of newborns (odds ratio [OR], 0.1) and the incidence of EOGBS disease (OR, 0.17), providing that there has been at least 2 hours of exposure to the prophylactic antibiotics during labour. 4 However, which screening method to use to identify high-risk women is controversial. The clinical risk strategy, which is used in the UK, was recommended by the Royal College of Obstetricians and Gynaecologists,5 while the universal swab-based strategy, which is used in the US and some European countries,6 was recommended
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GBS culture remains the reference standard for the detection of GBS colonization in pregnant women.

Table 1. Clinical risk factors for early-onset group B Streptococcus (GBS) disease A previous delivery of a newborn with GBS disease Antenatal GBS bacteriuria Membrane rupture of 18 hours or more Gestation < 37 weeks Intrapartum fever

administration of IAP.7 If the GBS screening is negative, the risk of EOGBS disease will be low even if the woman has one of the risk factors.13 If the vaginal/rectal swab shows the presence of GBS, antenatal antibiotics treatment cannot prevent EOGBS disease because per oral antibiotic treatment does not eliminate vaginal or rectal colonization.2 On the other hand, treatment of

Table 2. Universal swab-based screening

urinary tract infection or asymptomatic bacteriuria with GBS during pregnancy is indicated.14

1. Routine vaginal/rectal swab for GBS screening in women at 3537 weeks of gestation. 2. Give intrapartum antibiotics a) if the vaginal/rectal swab or urine cultures show the presence of GBS, or b) if the woman has given birth to an infant with invasive GBS disease, or c) if the GBS status is unknown, and a risk factor (as in Table 1) is present.
GBS = group B Streptococcus.

However,

universal

swab-based

strategy may not be accepted by some women because giving IAP in screen-positive cases will affect their autonomy and the feasibility of home birth. Side effects of IAP include anaphylaxis (1 in 10,000) or rarely death (1:100,000). Besides, increasing use of IAP can lead to an increase in Gram-negative or drug-resistant early-

CLINICAL RISK FACTORS


The clinical risk factors for EOGBS disease are well known and are listed in Table 1.
8,9

colonized with GBS at delivery. Besides, the risk-based approach may inappropriately expose 6585% of women with risk factors who are GBS-negative to antibiotics.
11

onset neonatal infection. 1517 Furthermore, there will still be affected infants who lack the typical intrapartum risk factors for GBS infection, are born to mothers with a negative GBS screen, or represent missed opportunities for prevention.18 Health-care providers should remain alert for signs of sepsis in any newborn infant.

Under the risk-based strategy, IAP is given to a woman without taking a swab if she has one or more of the risk factors. If a woman gives a history of maternal GBS colonization in her previous pregnancy but without neonatal disease, prenatal Current American and Canadian guidelines recommend routine vaginal/rectal 3537 weeks of gestation (Table 2).7,12 If the vaginal/rectal swab or urine cultures show the presence of GBS, or if the woman has given birth to an infant with invasive GBS disease, IAP will be given to the mother.
7,12

UNIVERSAL SWAB-BASED STRATEGY

UNIVERSAL SCREENING OR GBS screening will be required in her cur- swab for GBS screening of women at NOT?
rent pregnancy as the recurrence risk is more than one-third.10 If the GBS status is unknown during term labour in the current pregnancy, IAP will be given.
10

Whether to implement universal swabbased strategy or not depends on the local incidence of EOGBS disease, the prevalence of clinical risk factors in EOGBS disease, and the current obstetric practice. In the US, universal swab-based strategy has

However, this risk-based strategy cannot identify a subset of pregnant women who do not have any risk factors but are
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If the GBS status is unknown,

risk factors will be used to determine the

Continuing Medical Education

been adopted because of the high prevalence of EOGBS (1.8 per 1,000 births) and low prevalence (38%) of clinical risk factors in EOGBS disease. This swab-based strategy can prevent 75% of EOGBS disease by giving IAP to 31% of pregnant women.11 On the other hand, the clinical riskbased strategy has been recommended in the UK because of the low prevalence of EOGBS disease (0.5 per 1,000 births) even in the absence of systematic screening or widespread IAP and high prevalence (6070%) of clinical risk factors in EOGBS disease. This risk-based strategy can pre5

Table 3. Rapid test for group B Streptococcus

1. Fluorescence in situ hybridization 2. Latex agglutination test 3. Optical immunoassays and enzyme immunoassays 4. DNA probes 5. Nucleic acid amplification tests

needed for taking lower vagina swabs. Taking rectal swabs may cause discomfort or pain. An alternative is to take perineal swabs which may be preferred by women. A recent study showed that agreement was high (96%) between the vaginalrectal and the vaginalperianal collection methods.24 However, data are still limited. It is unclear whether it is cost-effective to add a routine urine test for asymp tomatic bacteriuria on top of vaginalrectal swabs at 3537 weeks gestation.
7

ate non-nutritive transport medium which can help sustain the viability of GBS in settings where immediate laboratory processing is not possible. 27 If processing is delayed, refrigeration (at 4C) will be used for storage. Processing the swabs within 24 hours of collection is recommended.28 Alternatively, the swabs can be placed into the enrichment broth immediately after collection. The use of selective broth media can facilitate GBS isolation by preventing the overgrowth of other commensal bacteria in vagina/rectum.29 Selective broth medium, such as Todd-Hewitt broth supplemented with nalidixic acid and either gentamicin or colistin, is inoculated and incubated at 3537C in ambient air or 5% CO2. The broth is then subcultured to a blood agar plate. The latter is inspected for GBS after incubation for 1824 hours. If GBS is not identified, re-incubation and re-inspection will be required at 48 hours.

vent 67% of EOGBS by giving IAP to 17% of pregnant women. effective in the UK. 19
11

Universal swab-

based strategy was found to be not cost-

WHICH SITE?
GBS colonization in the maternal gastrointestinal and/or genital tracts is a prerequisite for EOGBS disease. The colonization can be permanent, intermittent or transient. The colonization rate varies from 10% to 30%.2022 Perinatal colonization rate is around 50%, but only 1% becomes infected. To increase the detection rate of GBS colonization, swabs are taken from both the lower vagina (vaginal introitus) and the rectum (through the anal sphincter) instead of from one site alone. The use of
23

BY WHOM?
The vaginalrectal swabs are usually taken by a health-care provider. After having been given appropriate instructions, pregnant women can collect their own vaginalrectal screening specimens and give similar GBS yield.
26 25

However, they

may prefer a health professional to collect their swabs. Less-educated women may be more reluctant to collect their own samples. 25

two separate swabs is preferred over the use of one swab for both sites because of hygienic problem. To save laboratory cost, these two swabs can be stored in one transport medium as there is no need to differentiate between these two sites for screen-positive cases. A speculum is not

WHEN TO TAKE THE SWABS?


A recent systematic review in 2010 con-

PROCESSING
The swabs will be placed into an appropri-

firms the recommendations to screen for GBS at 3537 weeks gestation.30 The negative predictive value of GBS cultures
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performed within 5 weeks before delivery is very high (9598%) but declines beyond 5 weeks. GBS colonization early in pregnancy is not predictive of EOGBS disease because the coloniza tion can be transient.31 It will be appropriate to take a swab for GBS screening at 3537 weeks. However, there are two disadvantages. First, women who deliver before 35 weeks of gestation are not screened for GBS, but preterm newborns are at high risk of developing EOGBS disease.32 Second, up to 67% of infants with EOGBS were delivered by mothers who were negative on prenatal GBS screening.18 About 6% of GBS carriers remaining undetected in antenatal cultures. 30 GBS colonization can be intermittent during pregnancy. A change in the GBS colonization status from screening to delivery can occur in 9% of women.33 Consequently, under- or overtreatment with IAP may be resulted. Although the results of intrapartum swabs can reflect the GBS status more accurately than those of antepartum swabs,34 the culture method may not provide a timely result to guide IAP. shown that the rapid tests (Table 3), including fluorescence in situ hybridization, latex agglutination test, optical immunoassays and enzyme immunoassays, were not sensitive and specific enough to replace the established culture method.
3541

It is recommended that a swab for GBS screening be taken at 3537 weeks gestation.

viable or low-count bacteria 44 and is not affected by the presence of blood, meconium, or amniotic fluid. 33 The turnaround time of this rapid real-time PCR test can be within 1 hour.45 More data are needed. However, there are concerns on the real-world turnaround time, lack of antimicrobial susceptibility, availability of 24hour service, staffing requirements, and costs. Universal screening using a rapid test was not cost-effective, based on its current sensitivity, specificity and cost. 41 A rapid test may be useful for women at term with unknown GBS status and without risk factors. On the other hand, the current evidence does not support their use in replace m ent of antenatal culture or risk-based assessment of women with

CULTURE OR RAPID TEST?


GBS culture remains the reference standard for the detection of GBS colonization, but it usually takes 2472 hours to get the results. Therefore, culture-based testing is suitable for antepartum but not intrapartum screening. Ideally, the use of a highly sensitive and specific test with rapid turnaround time can assess intrapartum GBS colonization and hence guide IAP. Studies have
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Recently, molecular testing meth42

ods have been developed, including DNA probes and nucleic acid amplification
43

tests (NAAT) such as polymerase chain reaction (PCR). The performance of commercially available NAAT on non-enriched samples was variable and not adequate in comparison with culture. While the sensitivity of NAAT for GBS can be as high as 92.5100.0% with use of an enrichment step, the latter increases the turnaround time.
7,42

A rapid PCR test can detect non-

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unknown GBS status during intra partum.

weeks, and then discontinued subsequent- Yuk Hospital to determine the cost-effecly if the woman is not in true labour or if tiveness of prenatal universal screening the GBS culture is negative. GBS screening for GBS. During the study period from April should be repeated at 3537 weeks gesta- 2009 to March 2010, all pregnant women tion. seeking antenatal care were invited to participate in this study. GBS screening was performed according to the 2002 CDC guidelines. 47 All the swab specimens were sent to the microbiology laboratory of Queen Mary Hospital for testing for GBS. IAP was given to screen-positive women. Newborn infants born to mothers with GBS colonization were managed according to a protocol.

THE EFFECTS OF UPDATED CDC GUIDELINES7 ON OBSTETRIC PRACTICE


Bacteriuria To ensure proper testing, pregnancy should be specified when sending urine samples to a laboratory. The latter should report GBS in urine culture specimens when present at concentrations of 10 4 colony-forming units/mL in pure culture or mixed with a second microorgan ism. EOGBS is associated with maternal GBS bacteriuria (generally >105 colony-forming units/mL of urine).46 Few data are available on the risk with low (< 10 4) colony-count GBS bacteriuria. 46

Antibiotic Susceptibility To ensure laboratory testing for antimicrobial susceptibility to clindamycin, penicil- UNIVERSAL PRENATAL lin-allergic history, if any, should be speci- SCREENING FOR GBS IN fied on antenatal swabs for GBS screening. HONG KONG Intra Partum NAAT can be used to detect GBS in women with unknown GBS status and without any risk factors during intra partum. However, NAAT testing is optional, and its availability is limited. Threatened Preterm Labour If a woman is admitted with signs and symptoms of labour before 37 weeks gestation, GBS screening should be performed unless it was performed within 5 weeks. IAP should be given for unknown GBS status or a positive GBS screen within 5

Preterm Prelabour Rupture of Membranes If a woman is admitted with leaking before 37 weeks gestation, GBS screening should be performed unless it was performed within 5 weeks. If antibiotics are given to prolong latency for preterm prelabour rupture of membranes, the antibiotics should also be able to cover GBS adequately. Otherwise, an additional GBS prophylaxis should be given for 48 hours unless a GBS screen performed within the preceding 5 weeks was negative. GBS testing results should not affect the duration of antibiotics which are given to prolong latency.

In the past, all the public hospitals in Hong Kong used the clinical risk-based strategy to prevent EOGBS disease, and the incidence of EOGBS was around 0.71.1 per 1,000 births. A working group including obstetricians, paediatricians, and microbiologists was formed to study the prevention strategy in 2008.

Pilot Study There are racial or ethnic differences in EOGBS disease. Because of the lack of local data, a 1-year pilot study was conducted in Queen Mary Hospital and Tsan

Maternal GBS Colonization Rate During the pilot project which involved 3,908 pregnant women, 90% or 3,542 were eligible for screening at 3537 weeks gestation. After explanation and counseling on GBS screening by a midwife, 82% of these eligible women accepted the screening. The total number of women who underwent GBS screening was 2,890. The main reasons for declining GBS screening included (1) unwillingness to undergo screening (35.4%), (2) screening done privately (24.7%), (3) screening deemed unnecessary (20.4%), (4) planned elective Caesarean section (10.4%), and (5) plan to deliver in a private or other hospital (8.2%). We noticed a low screen-positive rate (4.2%) in the first month of screening. After reviewing the procedures of swab taking, transport medium and laboratory testing, the screen-positive rate increased to around 9.5% in subsequent months. The overall incidence of maternal GBS colonization was 9.6%. This was consistent with the results of another local study that the prevalence
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of GBS on booking was 10.4%.22 Like another local study,


22

ance to the protocol was, in general, good the GBS except for one screen-positive case in which IAP was not given. Fortunately, the neonate was not infected. There were no adverse events or complaints by patients.

mestic product), over 80% of simulations found that the swab-based strategy was more cost-effective than the current clinical risk factor-based strategy. In the UK, a cost-effectiveness study has shown that culture-based testing of women with no risk factors or rupture of membranes 18 hours with treatment for all preterm and high-risk term women would be the most cost-effective strategy.19 GBS screening in high-risk women would not be cost-effective, as even those with negative results would be better off treated to reduce the risk of EOGBS disease.

colonization rate was significantly higher in health-care professionals (19.4%) than in housewives (7.5%) (P = 0.004). The GBS colonization rate was also higher in women with a parity of 3 or above (27.3%) than women with a parity below 3 (9.9%) (P < 0.001). However, either a health-care professional or a woman with a parity of 3 or above was not a good screening marker as they constituted only a small proportion of the pregnant women. Surprisingly, a risk factor was present in only 12.9% of women with GBS colonization. There was no major maternal complications related to GBS.

COST-EFFECTIVENESS ANALYSIS
The cost-effectiveness analysis was performed by the Department of Community Medicine using a prediction model. This modelling study has shown that, based on the best evidence we have available at present, the swab-based strategy in Hong Kong would likely cost more but probably avoid more cases of EOGBS than the cur-

CONCLUSION
Whether to implement universal swabbased strategy or clinical risk-based strategy depends on the local incidence of EOGBS disease, the prevalence of clinical risk factors in EOGBS disease, and the current obstetric practice. Universal swabbased strategy and clinical risk-based strategy differ in the proportion of women being given IAP, and cost-effectiveness. It seems that the universal swab-based strategy would likely cost more but probably avoid more cases of EOGBS disease than the clinical risk factor-based strategy. However, universal prenatal screening cannot prevent all affected infants because of a false-negative result, the lack of the typical intrapartum risk factors for GBS infection, or missed opportunities for screening. Improved management of preterm deliveries and improved communication, collection, processing and reporting of culture results may prevent additional

Babies During the pilot project, a total of 1,770 swabs (including gastric aspirate, ear, and blood) were taken from the babies. There were three cases of EOGBS disease presented with septicaemia. One of them developed meningitis as well. In two of them, the mothers declined screening while the screening result was negative in the remaining one. This result was compatible with the 4% false-negative rate which was reported in the literature.18 There was no neonatal mortality related to GBS.

rent clinical risk factor-based strategy. This finding is consistent with a study in the US that universal screening was predicted to prevent more EOGBS disease, but at a larger cost than the risk-factor strategy (75% vs 54%; US$12,000 vs US$3,000).
11

The incremental cost-effectiveness ratio (ICER) was HK$255,367 (about US$32,000) per life-year gained. The ICER was most sensitive to the rates of maternal colonization, vertical transmission, mortality, and disability. The effectiveness of IAP and the rate of receiving IAP were less important. Varying the number of days in hospital and the proportion of days in the neonatal intensive care unit for EOGBS cases did not have an important impact on the cost-effectiveness of the strategies. The cost-effectiveness acceptability curves show that using the World Health Organization benchmark for value of a lifeyear (one to two times per capita gross do-

LOGISTIC PROBLEMS
There were no major logistic difficulties. Around 8% of women did not return at 35 37 weeks gestation for GBS screening. Tracing the GBS reports from our electronic medical system was preferred over paper records, which might not be available during the intrapartum period. The compliJPOG SEP/OCT 2013 218

Continuing Medical Education

cases of EOGBS disease.7,48 Ideally, a highly sensitive and specific ( 90%) but low-complexity test with a rapid turnaround time (< 30 minutes) can be used to determine intrapartum GBS status, as well as mutations likely to confer resistance to clindamycin and/or erythromycin. A rapid test may be useful for women at term with unknown GBS status and without risk fac-

tors. However, using a rapid test for universal screening was not cost-effective based on its current sensitivity, specificity and cost. 41 Further studies are required.

Professor in the Research Centre of Infection and Immunology, Department of Microbiology, The University of Hong Kong. Dr Wong is Consultant in the Department of Paediatrics and Adolescent Medicine, and Dr Li is Associate Consultant and Honorary Clinical Assistant Professor in the Department of Obstetrics and Gynaecology, Queen Mary Hospital. Dr Law is Consultant in the Department of Paediatrics, Queen Elizabeth Hospital. Dr McGhee is Professor in the Department of Community Medicine, School of Public Health, The University of Hong Kong, Hong Kong.

About the Authors


Dr Leung is Chief of Service and Consultant in the Department of Obstetrics and Gynaecology, and Dr Ma is Consultant in the Department of Obstetrics and Gynaecology, Queen Elizabeth Hospital. Dr To is Clinical Assistant

References
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Peltroche-Llacsahuanga H, Fiandaca M, von Oy S, Ltticken R, Haase G. Rapid detection of Streptococcus agalactiae from swabs by peptide nucleic acid fluorescence in situ hybridization. J Med Microbiol 2010;59:179184. 43. Block T, Munson E, Culver A, Vaughan K, Hryciuk JE. Comparison of carrot broth- and selective Todd-Hewitt broth-enhanced PCR protocols for real-time detection of Streptococcus agalactiae in prenatal vaginal/anorectal specimens. J Clin Microbiol 2008;46:36153620. 44. Mullen WMC, Sharma V, Morrison J, Barry T, Maher M, Smith T. Evaluation of a novel real-time PCR test based on the ssrA gene for the identification of group B streptococci in vaginal swabs. BMC Infect Dis 2009; 9:148. 45. Alfa MJ, Sepehri S, Gagne PD, Helawa M, Sandhu G, Harding GKM. Real-time PCR assay provides reliable assessment of intrapartum carriage of group B Streptococcus. J Clin Microbiol 2010;48:30953099. 46. Persson K, Bjerre B, Elfstrom L, Polberger S, Forsgren A. Group B streptococci at delivery: high count in urine increases risk for neonatal colonization. Scand J Infect Dis 1986;18:525531. 47. Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC. MMWR Recomm Rep 2002;51:122. 48. Van Dyke MK, Phares CR, Lynfield R, et al. Evaluation of universal antenatal screening for group B streptococcus. N Engl J Med 2009;360:26262636.

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Program pendidikan kedokteran berkelanjutan ini dipersembahkan oleh MIMS, bekerjasama dengan Ikatan Dokter Indonesia. Setelah membaca artikel Screening for Group B Streptococcus in Pregnancy, jawab pertanyaan berikut kemudian kirimkan dengan menggunakan formulir jawaban yang sudah disediakan ke CME Journal of Paediatrics, Obstetrics & Gynaecology, untuk mendapatkan 5 SKP.

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Screening for Group B Streptococcus in Pregnancy


Jawab pertanyaan di bawah ini dengan Benar atau Salah
1. Maternal temperature of 38.8C during the intra partum is a risk factor for early-onset group B Streptococcus (GBS) disease. 2. Administration of intrapartum antibiotic prophylaxis for GBS is indicated in a woman who goes into labour at 38 weeks gestation with unknown GBS status and gives a history of maternal GBS colonization in her previous pregnancy but without neonatal disease. 3. If the vaginal/rectal swab shows the presence of GBS, antenatal antibiotics treatment will be required to eradicate GBS. 4. For GBS screening, swabs are taken from both the high vagina and the anus. 5. Delayed processing of the swabs for more than 24 hours does not affect the laboratory detection of GBS. 6. It is recommended to take swabs for GBS screening at 3537 weeks gestation. 7. The performance of a rapid test for GBS on non-enriched swab samples is as good as the culture method. 8. If a woman is admitted with painful uterine contractions at 35 weeks gestation and unknown GBS status, GBS screening should be performed and intrapartum antibiotic prophylaxis for GBS given. 9. GBS colonization rate was signicantly higher in health-care professionals than in housewives in Hong Kong. 10. In the UK, culture-based testing of women with no risk factors while being given intrapartum antibiotics for GBS for all preterm and high-risk term women is the most cost-effective strategy.

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