JPOG February 2013 HK

JAN/FEB 2013 jan/feb 2012 Vol. 39 38 No.
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JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY
Your partner in paediatric and O&G practice
ISSN 1012-8875 (HONG KONG)
JOURNAL WATCH
PAEDIATRICS
Common Sleep Disorders in Children

OBSTETRICS
Bleeding Disorders in Pregnancy Postpartum Pyrexia

CME ARTICLE
Endometrial Carcinoma
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J AN/ FEB Vol. 39
2013 No. 1
Journal Watch
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Treatment for CIN and preterm birth Fetal macrosomia without maternal diabetes: Effect of low glycaemic index diet in pregnancy Respiratory rate corrected for age and temperature in diagnosis of lower respiratory infection in children
Leukaemia and brain tumour risks from childhood CT scans Paediatric ventricular assist device prolongs survival Intermittent preventive treatment for malaria in infancy: No effect on immunization responses Strict blood glucose control in ICU after paediatric cardiac surgery: No benefit
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Effectiveness of rotavirus vaccination in a high-income country Inhaled steroid in childhood and adult height Violence against handicapped children DTaP vaccine in USA: Re-emergence of pertussis after fifth dose
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 Associate 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 Kwong Wah Hospital, 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 Perla D Santos Ocampo University of the Philippines Associate Professor Alex Sia KK Womens and Childrens Hospital, Singapore
Dr Raman Subramaniam Fetal Medicine and Gynaecology Centre, Malaysia Professor Walfrido W Sumpaico MCU-DFT Medical Foundation, Philippines Professor Cheng Lim Tan KK Womens and Childrens Hospital, Singapore Associate Professor Kok Hian Tan KK Womens and Childrens Hospital, Singapore Dr Surasak Taneepanichskul Chulalongkorn University, Thailand Professor Eng-Hseon Tay Thomson Womens Cancer Centre, Singapore Professor PC Wong National University of Singapore Dr 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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Important benefits for women who quit smoking early

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Elvira Manzano
moking nearly triples the risk of premature death in women and quitting the habit well before middle-age reduces this risk, according to the Million Women Study. In this prospective study, the largest in the history of studying the dangers of smoking, 12-year mortality rates among women who smoked throughout their adult years were almost three times higher than those of women who never smoked (rate ratio 2.97, 95% CI, 2.88-3.07). Even light smokers (those who smoked fewer than 10 cigarettes per day) had twice the mortality rate of never-smokers (rate ratio 1.98, 95% CI, 1.912.04). [Lancet 2012.DOI.org/10.1016/S01406736(12)61720-6] What was encouraging, however, was the positive effect that quitting seemed to have on womens life span. Stopping the habit before age 40 avoided more than 90 percent of excess mortality from cigarettes. Quitting before age 30 avoided 97 percent of this added risk. Smokers who stop before reaching middle-age will on average gain about an extra 10 years of life, said study author Professor Sir Richard Peto, of the University of Oxford, Oxford, UK. This does not, however, mean that it is safe to smoke until age 40 and then stop, the authors warned. Decades later throughout life, women who smoked and stopped still have 1 to 2 times the mortality rate of neversmokers. For those who continued to smoke past age 40, the risk is 10 times greater. The study enrolled 1.3 million women (age 50-65) in the UK followed for 12 years. At baseline, 20 percent were smokers, 28 percent were former smokers and 52 percent never smoked.
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Women who quit smoking early can avoid a three-fold increased risk of death, according to the Million Women Study. By 2011, 66,000 had died. Compared with non-smokers, smokers lost at least 10 years of life and died from smoking-related diseases such as lung cancer, heart disease and stroke. While the absolute hazards of prolonged smoking are substantial, so are the benefits of quitting. Even cessation at about 50 years of age avoids at least two-thirds of the continuing smokers excess mortality in later middle age, the authors said. The benefits are, however, greater in those who quit earlier. In a linked comment, Dr. Rachel Huxley, from the University of Minnesota, Minneapolis, US, and Dr. Mark Woodward, from the University of Sydney, Australia, welcomed the findings. Aside from its impressive sample size, the Million Women Study is distinct from previous large cohortsand superior for assessment among women of the full hazards of prolonged smoking and the full benefits of long-term cessation because the participants were among the first generation of women in the UK in which smoking was widespread in early adult life, and although many continued smoking, many stopped before age 30 or 40 years. The results emphasize the need for effective sex-specific and culturally-specific tobacco control policies that encourage adult smokers to quit and discourage children and young adults from starting smoking, they concluded.
DOH releases advisory on stem cell therapies
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COnFeRenCe
Multivitamins may protect against cancer

Rajesh Kumar
aily multivitamin use for more than a decade caused a modest but statistically significant 8 percent reduction in all cancers among men in a large randomized, double-blind, placebo control trial. Researchers analyzed data from the Physicians Health Study II involving 14, 641 male US physicians aged 50 years or older, including 1,312 men with a history of cancer. The men were randomized in 1997 to receive either multivitamin supplements or placebo
Monoclonal antibody aids statin-refractory patients
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and were followed up through June 1, 2011. [JAMA 2012; DOI:10.1001/jama.2012.14641] The primary outcome was total cancer (excluding non-melanoma skin cancer), with prostate, colorectal, and other site-specific cancers among the secondary end points. During the trial, 2,669 cases of cancer were detected, including 1,373 cases of prostate cancer and 210 cases of colorectal cancer, with some men experiencing multiple events. Men taking a daily multivitamin had a statistically significant reduction in the in-
cidence of total cancer compared with those taking placebo (17.0 and 18.3 events, respectively, per 1,000 person-years; hazard ratio [HR] 0.92; 95% CI, 0.86-0.998; P=0.04). The multivitamin group had a similar reduction in total epithelial cell cancer, but not in other site specific cancers such as colorectal, lung and bladder cancer. The men who had a history of cancer at baseline also saw a reduction in their total cancer risk but this was not any different from the case of healthier men. Turn to page 2 >>
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J AN/ FEB Vol. 39
2013 No. 1
Review Article Paediatrics
Common Sleep Disorders in ChildrenDiagnosis and Management

There is an increasing awareness of the need for good sleep in children. Children with poor/insufficient sleep or sleep-disordered breathing can have mild to serious sequelae. This article discusses the common paediatric sleep disorders as well as their diagnosis and management. Petrina Wong Poh Chen, Teoh Oon Hoe, Chay Oh Moh
Review Article Obstetrics
15 Bleeding Disorders in Pregnancy During pregnancy, the physiological changes in the haemostatic system tend to improve the mild inherited
bleeding disorders. However, thrombocytopenia and coagulation problems unique to pregnancy may occur. This review discusses and provides recommendations for the management of bleeding problems seen in pregnancy. Eleftheria Lefkou, Beverley J Hunt
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PUBLISHER: Journal of Paediatrics, Obstetric & Gynaecology (JPOG) is published 6 times a year by UBM Medica, a division of United Business Media. CIRCULATION: JPOG is a controlled circulation for medical practitioners in South East Asia. It is also available on subscription to members of allied professions. SUBSCRIPTION: The price per annum is US$42 (surface mail, students US$21) and US$48 (overseas airmail, students US$24); back issues US$8 per copy. EDITORIAL MATTER published herein has been prepared by professional editorial staff. Views expressed are not necessarily those of UBM Medica. Although great care has been taken in compiling and checking the information given in this publication to ensure that it is accurate, the authors, the publisher and their servants or agents shall not be responsible or in any way liable for the continued currency of the information or for any errors, omissions or inaccuracies in this publication whether arising from negligence or otherwise howsoever, or for any consequences arising therefrom. The inclusion or exclusion of any product does not mean that the publisher advocates or rejects its use either generally or in any particular field or fields. COPYRIGHT: 2013 UBM Medica. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, in any language, without written consent of copyright owner. Permission to reprint must be obtained from the publisher. ADVERTISEMENTS are subject to editorial acceptance and have no influence on editorial content or presentation. UBM Medica does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature. Philippine edition: Entered as second-class mail at the Makati Central Post Office under Permit No. PS-326-01 NCR, dated 9 Feb 2001. Printed by Fortune Printing International Ltd, 3rd Floor, Chung On Industrial Building, 28 Lee Chung Street, Chai Wan, Hong Kong.
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From the research bench to your patients bedside JPOG raises the quality of life of women and children in Asia. Pick up a copy today and start earning CME points. For further details, visit www.jpog.com today.
J AN/ FEB Vol. 39
2013 No. 1
Review Article Obstetrics
28 Postpartum Pyrexia Postpartum pyrexia is a common condition that is sometimes associated with serious maternal morbidity
and occasional mortality. Most cases are due to underlying genital tract infection, but there are a wide variety of other possible causes that may not always be clinically obvious. Kevin G Glackin, Margaret Ann Harper
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Continuing Medical Education
37 Endometrial Carcinoma Recent clinical studies have raised queries and challenges to the conventional treatment approach to
endometrial carcinoma. This article gives an overview of this disease, discusses the controversies, summarizes the current position, and highlights the possible treatment strategies in the future. TH Cheung
37
The Journal of Paediatrics, Obstetrics and Gynaecology contains articles under licence from UBM Media LLC. The articles appearing on pages 4953, and pages 6780 are reprinted with permission of Consultant for Pediatricians. Copyright 2011 UBM Media LLC. All rights reserved.
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quality-managed colposcopy clinics.
OBSTETRICS
The apparent increase in risk of preterm delivery after colposcopy and biopsy or treatment for CIN may be due to confounding.
PAEDIATRICS
Treatment for CIN and preterm birth
Castanon A et al. Risk of preterm birth after treatment for cervical intraepithelial neoplasia among women attending colposcopy in England: retrospective-prospective cohort study. BMJ 2012; 345 (Sept 15): 15 (e5174); Kyrgiou M et al. Increased risk of preterm birth after treatment for CIN. Ibid: 8(e5847) (editorial).
Respiratory rate corrected for age and temperature in diagnosis of lower respiratory infection in children
Respiratory rate is important in the diagnosis of
Fetal macrosomia without maternal diabetes: Effect of low glycaemic index diet in pregnancy
Fetal macrosomia is often associated with maternal diabetes and is associated with increased risks to mother and fetus. Researchers in Dublin, Ireland, have assessed the effect of a low glycaemic index diet during pregnancy in women at risk of fetal macrosomia. A total of 800 women with a history of feA study at 12 National Health Service hospitals in England has suggested that any increase in premature delivery among women undergoing colposcopy and biopsy or treatment for cervical intraepithelial neoplasia (CIN) may be a result of statistical confounding. The retrospectiveprospective study included 44,210 women who had had a cervical biopsy at colposcopy during 19872009 with follow-up data for up to 10 years. There were 18,441 singleton births at between 20 and 43 weeks of gestation. Colposcopy before delivery rather than after increased the risk of preterm birth (< 37 weeks) by 33%. Among women whose delivery preceded colposcopy, having treatment for CIN rather than biopsy only, increased the risk by 19%. After adjustment for biopsy or treatment and colposcopy and for colposcopy before or after delivery, there was, however, no increase in preterm delivery. The risk of preterm birth was less for women treated at tal macrosomia (birthweight, > 4 kg) in their first pregnancy were randomized early in their second pregnancy to a eucaloric, low glycaemic index diet or routine antenatal care. Mean birthweight was similar in the two groups (4,034 g in the diet group and 4,006 g in the control group). Weight gain during pregnancy was less in the diet group (12.2 vs 13.7 kg). Glucose intolerance was diagnosed in 21% vs 28%, a significant difference. There were no adverse effects attributed to the diet. A low glycaemic index diet in pregnancy for women with a previous history of fetal macrosomia but without diabetes did not reduce birthweight but did reduce maternal weight gain in pregnancy and the rate of maternal glucose intolerance.
Walsh JM et al. Low glycaemic index diet in pregnancy to prevent macrosomia (ROLO study): a randomised control trial. BMJ 2012; 345 (Sept 22): 17 (e5605).
lower respiratory tract infection in children, but it may be affected by age and body temperature. Data from a single childrens emergency department in the Netherlands have been used to derive age- and temperature-dependent reference values for respiratory rate in febrile children. The derivation population consisted of 1,555 children under the age of 16 years. Centile charts for respiratory rate were constructed for children of different ages and body temperatures. A validation population of 671 children was used to compare respiratory rate and temperature values for children of different ages with pneumonia, other lower respiratory infections, and non-lower respiratory infections. Overall, respiratory rate increased by 2.2 breaths/min with every 1C rise in body temperature. Respiratory rate values above the 97th centile on the new age- and temperature-dependent charts were more useful in the diagnosis of lower respiratory tract infection than was use of existing respiratory rate thresholds but could not discriminate between pneumonia and other lower respiratory tract infections. They gave a specificity of 0.94 and a positive likelihood ratio of 3.66. In infancy, the 97th centile value for respiratory rate was 69 breaths/min with a temperature of 37.0C to 37.9C and 75 breaths/min with a temperature of 39.0C to 39.9C. At ages 5 to 16 years the corresponding values were 36 and 44 breaths/min. Centile charts for respiratory rate taking into account age and body temperature may be useful
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in the diagnosis of lower respiratory tract infection in children. The data should be used only to add strength to diagnosis of lower respiratory infection and not to dismiss it.
Nijman RG et al. Derivation and validation of age and temperature specific reference values and centile charts to predict lower respiratory tract infection in children with fever: prospective observational study. BMJ 2012; 345: (July 28): 15 (e4224): Kilonback A. Assessing respiratory rate for children with fever. Ibid: 8 (e4249)
patients for the leukaemia study and 176,587 for the brain tumour study about people who had a first CT scan between 1985 and 2002 when they were < 22 years old. Follow-up for leukaemia began 2 years after the first scan and for brain tumours after 5 years, with an average follow-up of 10 years. Compared with a cumulative CT radiation dose of < 5 mGy, a cumulative bone marrow radiation dose
lar assist device as a bridge to heart transplantation in children. The EXCOR Pediatric Ventricular Assist Device (Berlin Heart GmbH, Berlin, Germany) has been assessed in a multicentre, single-group study.
Leukaemia and brain tumour risks from childhood CT scans
of 30 mGy or greater increased the leukaemia risk by a factor of 3.18 and a cumulative brain dose of 5074 mGy increased the brain tumour risk by a factor of 2.82. CT scanning in childhood is associated with small but significant increases in risk of leukaemia or brain tumour. The absolute risks are small. For every 10,000 first head scans in children under the age of 10 years, there might be one extra case of leukaemia and one of brain tumour. The benefits of CT scanning will usually outweigh the risks, but dosage should be kept to a minimum and the use of other imaging techniques should be considered if appropriate.
Pearce MS et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet 2012; 380: 499505; Einstein AJ. Beyond the bombs: cancer risks of low-dose medical radiation. Ibid: 455457 (comment).
The study included 48 children up to the age of 16 years in two groups according to body surface area (< 0.7 m 2 or 0.7 to < 1.5 m 2) with 24 in each group. Survival was compared with that of propensity scorematched historical control groups who underwent ECMO as a bridge to heart transplan-
Children are more sensitive to radiation than adults, and it is important to keep radiation exposure in children to a minimum. There has been controversy about the risk involved in computed tomographic (CT) scanning. Previous risk estimates of the risk of cancer following CT scans have been based on projections from Japanese data after the atomic bombs. Now, a study of data from National Health Service (NHS) hospitals in England, Wales, and Scotland has provided direct correlation between radiation dosage from CT scans in childhood and later risk of leukaemia or brain tumour. With the use of hospital records and NHS Central Registry, data were available for 178,604
Paediatric ventricular assist device prolongs survival

Heart failure is much less common in children than in adults but carries a poor prognosis. Heart transplantation in children is effective (83% survival at 3 years), but a paucity of donor hearts means a high waiting list mortality. Extracorporeal membrane means a high waiting list mortality. Extracorporeal membrane oxygenation (ECMO) may be used to keep some children alive until transplantation, but it can be used for only 1020 days, which is not long enough for many children. Researchers in North America have reported the use of a ventricu-
tation. Among children with a body surface area < 0.7 m2, median survival time had not been reached at 174 days whereas in the matched ECMO control group it was 13 days. Among children with a body surface area of 0.7 to < 1.5 m2, the corresponding median survival times were 144 days and 10 days, respectively. Major bleeding, infection, and stroke were common in both EXCOR device and ACMO groups. Use of the ventricular assist device increased survival times.
Fraser CD et al. Prospective trial of a pediatric ventricular assist device. NEJM 2012; 367: 532541; Addonizio LJ. Pediatric ventricular assist devices first steps for babies. Ibid: 576578 (editorial).
JPOG JAN/FEB 2013 2
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Intermittent preventive treatment for malaria in infancy: No effect on immunization responses
tions were available for 2,396 children, and IPTi did not reduce responses. IPTi does not impair responses to routine immunizations in infancy. Lancet commentators point out that there is uncertainty whether IPTi is associated with an increase in overall mortality. More data are needed.
Crawley J et al. Effect of intermittent preventive treatment for malaria during infancy on serological responses to measles and other vaccines used in the Expanded Programme on Immunization: results from five randomised controlled trials. Lancet 2012; 380: 10011010; Benn CS, Aaby P. Does IPTi decrease malaria morbidity but not mortality? Ibid: 958960 (comment).
control) vs 9.9% (standard care), a non-significant difference. There were no significant differences between the groups in mortality, length of stay on ICU, or rates of organ failure. Tight blood glucose control did not confer any clinical advantages.
Agus MSD et al. Tight glycemic control versus standard care after pediatric cardiac surgery. NEJM 2012; 367: 12081219; Kavanagh BP. Glucose in the ICU-evidence, guidelines and outcomes. Ibid: 12591260 (editorial).
Effectiveness of rotavirus vaccination in a high-income country Strict blood glucose control in ICU after paediatric cardiac surgery: No benefit
Hyperglycaemia is common in infants and young children recovering from cardiac surgery, but there is controversy about its treatment. Strict blood glucose control might provide some advantages, but Intermittent preventive treatment during infancy (IPTi) with sulfadoxinepyrimethamine has been shown to reduce the incidence of clinical malaria in infancy in countries with moderate or high malaria transmission. IPTi is given at 810 weeks, 1214 weeks, and 9 months at times of routine vaccination (second and third diphtheria-tetanus-pertussis doses and measles dose). It is not known whether IPTi could affect responses to immunization. Now, a study in Ghana, Tanzania, Mozambique, and Kenya (two sites) has shown that IPTi did not affect serological responses to vaccinations. A subset of 1,904 infants, out of 8,416 infants in five studies of IPTi, were included in the present study. Of these, 1,904,970 had received IPTi and 934 placebo. A non-protective response to measles vaccine was detected in 6.3% (IPTi) vs 6.4% (placebo). Use of drugs other than sulfadoxinepyrimethamine for IPTi did not affect the results. Serological response data for other vaccinathere is concern about insulin-induced hypoglycaemia. A trial in two US cardiac intensive care units (ICUs) has shown a low rate of severe hypoglycaemia with carefully monitored intensive glucose control but no clinical benefits. The trial included 980 children aged 036 months recovering from cardiac surgery with cardiopulmonary bypass in ICUs in Boston, Massachusetts, and Ann Arbor, Michigan. Randomization was to tight glucose control (target blood glucose, 4.4 6.1 mmol/L) with an insulin-dosing algorithm and a continuous subcutaneous blood glucose monitor, or standard care. Insulin was given to 91% in the tight control group and 2% of the standard care group. Blood glucose control was achieved earlier in the tight control group (6 vs 16 hours) and maintained for longer (50% vs 33% of the critical illness period). The rate of severe hypoglycaemia in the tight control group was 3%. The rates of health-careassociated infection on the ICU was 8.6% (tight Reports of the effectiveness of rotavirus vaccination have come largely from low- or middle-income countries. Now, a report from Belgium has shown that it is effective in a high-income country. The study included 215 children admitted to hospital with community-acquired, polymerase chain reactionconfirmed rotavirus gastroenteritis and 276 age- and hospital-matched controls, all from a random sample of 39 Belgian hospitals between February 2008 and June 2012. The effectiveness of two doses of monovalent rotavirus vaccine
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was 90% overall, 91% among children aged 311 months, and 90% among children aged 12 months or older. Rotavirus vaccination is effective in Belgium for the prevention of rotavirus gastroenteritis in young children leading to hospital admission.
The RotaBel Study Group. Effectiveness of rotavirus vaccination in prevention of hospital admissions for rotavirus gastroenteritis among young children in Belgium: case-control study. BMJ 2012; 345: (Sept 1): 13 (e4752): Patel MM. Rotavirus vaccination programmes. Ibid: 7(e5286) (editorial).
513 years with mild-to-moderate asthma were randomized to inhaled budesonide 200 g twice daily, inhaled nedocromil 8 mg twice daily, or placebo, for 46 years. The adult height of 943 participants (mean age, 24.9 years) was 171.1 cm in the budesonide group, 172.1 cm in the nedocromil group, and 172.3 cm in the placebo group. The difference of 1.2 cm between the budesonide and placebo groups was significant, but the 0.2 cm difference between nedocromil and placebo groups was not. For each microgram per kilogram of body
pared with other children, children with a disability were almost four times more likely to suffer violence of any kind, more than three times more likely to suffer physical violence, and almost three times more likely to suffer sexual violence. The analysis confirms the increased prevalence of violence in disabled children compared with other children, but much more needs to be known about risk factors and means of prevention.
Jones L et al. Prevalence and risk of violence against children with disabilities: a systematic review and meta-analysis of observational studies. Lancet 2012; 380: 899907; Lund EM, Vaughn-Jensen JE. Victimisation of children with disabilities. Ibid: 867869 (comment).
Inhaled steroid in childhood and adult height
weight increase in daily dose of budesonide in the first 2 years of treatment, there was a 0.1 cm reduction in final height. The reduction in final height with budesonide was similar to the reduction seen after 2 years of treatment. Inhaled steroid in childhood reduced attained height 2 years later and final height by an average of 1.2 cm.
Kelly HW et al. Effect of inhaled glucocorticoids in childhood on adult height. NEJM 2012; 367: 904912.
DTaP vaccine in USA: Reemergence of pertussis after fifth dose

In the USA, children receive five doses of the diphtheria, tetanus, acellular pertussis vaccine (DTaP) at 2, 4, 6 and 1518 months and at 46 years. Despite this, there has been a resurgence
Violence against handicapped children

Child abuse is common. It is estimated that in 2001, some 53,000 children were murdered and 223 million were sexually abused. About 5% of children (3% in high-income countries and up to 6% in low- or middle-income countries) have moderate or severe disability. It is known that adults with disability are particularly vulnerable to violence and is Children treated with inhaled steroid for asthma lose on average about 1.0 cm of growth in the first few years of treatment, but growth then resumes at a normal pace and the effect on adult height is uncertain. Now, a multicentre US trial has shown a reduction in final height of about 1 cm with inhaled steroid. In the Childhood Asthma Management Program (CAMP) trial, a total of 1,041 children aged suspected that the same applies to children with disability. A systematic review and meta-analysis of observational studies of violence in disabled children has confirmed this susceptibility whilst criticizing the quality of current evidence. The analysis included 17 studies. The prevalence of violence of any kind against children with any disability was 26.7%, for physical violence it was 20.4%, and for sexual violence 13.7%. Com-
of whopping cough and the duration of protection after the fifth dose has been questioned. Now, a report from California has suggested that protection deteriorates quite rapidly. The study, in the Kaiser Permanente organization, included children who had been fully vaccinated against pertussis using DTaP between 2006 and 2011. Cases were 277 children with pertussis confirmed by polymerase chain reaction testing, and there were 3,318 polymerase chain reaction negative controls and 6,086 matched population controls. The children with pertussis had received the fifth dose of DTaP at a younger age than the children in either set of controls. It was calculated that after the fifth dose, the risk of pertussis increased by 42% each year. New vaccines that give longer-lasting protection are needed.
Klein NP et al. Waning protection after fifth dose of acellular pertussis vaccine in children. NEJM 2012; 367: 10121019.
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The Changing Panorama Of Womens Health:
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Common Sleep Imaging Paediatric Disorders in Children Brain Tumours Diagnosis and Management
Tang Phua Hwee, MBBS, FRCR, MMed Diagnostic Radiology Petrina Wong Poh Chen, MBBS (Singapore), MRCPCH (UK); Teoh Oon Hoe, MBBS (Singapore), MMed (Paed), MRCPCH (UK); Chay Oh Moh, MBBS (Singapore), MMed (Paed), FAMS (Paed), FRCPCH
INTRODUCTION: SLEEP IS IMPORTANT IN CHILDREN

Interest in paediatric sleep disorders is increasing worldwide. There is evidence that there are significant short- to long-term consequences on the development, growth, and health in children with poor/insufficient sleep or sleep-disordered breathing. More caregivers are recognizing the importance of good sleep and are seeking medical advice for sleep problems in their children. Table 1 summarizes the wide range of physical and psychosocial health deficits that can be found in children with poor/insufficient sleep or sleep-disordered breathing.
Normal Sleep Sleep and wakefulness is regulated by the (1) circadian rhythm, which is entrained by the lightdark cycle, and (2) homeostatic process, which builds up the need for sleep during the waking hours. Normal sleep comprises two states: non-rapid eye movement (NREM) sleep, also known as quiet sleep (with stages N1, N2 and N3), and rapid eye movement (REM) sleep, otherwise known as active sleep. These states alternate cyclically across a sleep episode. NREM sleep is characterized by synchronized electroencephalography activity, muscle relaxation, and decreased heart rate, blood pressure and tidal volume. REM sleep resembles wakefulness with desynchronized electroencephalography activity, phasic events such as episodic bursts of rapid eye movement, but muscle atonia (a highly activated brain in a paralysed body). Sleep in children differs from sleep in adults in its architecture, sleep pattern, and behaviour. This is related to the maturation of the central nervous system and developmental changes that take place when one ages through the years.
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PAEDIATRIC S PAEDIATRICS
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Table 1. Impact of poor/insufficient sleep and sleep-disordered breathing in children
differentiation only develops between 6 weeks to 3 months old, with most babies being able to sleep through the night by 9 months old. Infants typically take two naps in the day (mid morning and afternoon) and do away with the morning nap by 18 to 24 months old. Average sleep duration over a 24-hour period at this stage ranges between 13 and 15 hours in infants below a year old to 12 hours in a 2-year-old toddler. At 3 to 5 years old, most children do away with naps and sleep an average duration of 1112 hours. School-going children require about 10 to 11 hours of sleep. Adolescents tend to have irregular sleep
Daytime somnolence Impaired memory and concentration Impaired motor skills Poor academic performance Mood disturbances (mood lability, poor emotional control, irritability) Disruptive behaviour (aggressiveness, impulsivity, hyperactivity) Negative parentchild relationships
Reduced immune function Increased risk of obesity/ metabolic conditions Cardiopulmonary complications Poor growth
The cycling of NREM and REM sleep is established by 3 to 4 months of age. Sleep usually begins in NREM sleep and progresses through deeper NREM sleep stages (N2 and N3) before the first episode of REM sleep occurring about 50 minutes later in children and 80 to 100 minutes later in adults. Thereafter, NREM and REM sleep cycles with a period of between 50 to 70 minutes in infants to 90 to 120 minutes in adults. Stage N3also called slow wave sleep (SWS)concentrates in the early NREM cycles, and REM sleep episodes lengthen across the night. An example of a sleep histogram is illustrated in Figure 1. Most children have sleep requirements that fall within a predictable range of hours based on their age, but each child is a unique individual with distinct sleep needs. There is no fixed number required by all children in a certain age group, but a guide to the approximate number of hours needed is as follows1: Newborns usually sleep in stretches of about 3 to 5 hours (shorter in breastfed babies) and are awake for 1 to 3 hours in between. This adds up to 16 to 20 hours in a 24-hour period. Daynight
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schedules. Most sleep less than 6 to 7 hours a night, although the ideal requirement should be 9 hours for their age. At the onset of puberty, they develop a 2-hour phase delay in their circadian rhythm, leading to a natural tendency to sleep late and, therefore, rise late.
Good Sleep Hygiene Advice for Children Keep consistent sleep and wake times daily, including over the weekends. Do not use the bed for any activity other than sleeping (eg, watching television, playing, eating). Avoid placing the computer, television, mobile phones, and other personal electronic devices in the bedroom. Do not use the bedroom for time-out or punishment. The childs bedroom should be conducive for sleeping at bedtimecool, quiet, and comfortable. A dim nightlight is acceptable for children afraid of the dark. Establish a predictable, relaxing pre-bedtime routine such as brushing teeth, changing into pyjamas, and reading a story. Avoid stimulating
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PA ED IATRICS PEER REVIEWED
Figure 1. Sleep histogram.
activities before sleep, such as watching exciting television programmes and playing games on personal electronic devices. Go to bed only when tired or sleepy; avoid spending too much time awake in bed. If the child is awake and unable to fall asleep after 20 minutes, consider letting him/her get out of bed to do low stimulation activity (eg, quiet reading) then return to bed later. This prevents the bed from being associated with sleeplessness. Transitional objects, like a toy, blanket or doll, are useful for young children who need to feel safe and secure when their caregiver is not physically present, and may aid in independent settling and self-soothing. Checks on the infant or toddler at night should be brief and non-stimulating. Avoid caffeine (coffee, tea, chocolate, energy drinks, and sodas) close to bedtime, as caffeine
can lead to difficulty falling asleep, shallow sleep, or frequent nocturnal awakenings.
Sleep Disorders Sleep disturbances are common in children of all ages and have been described in up to 45% in the population of healthy preschool and school-going children.24 These figures may even be an underestimate, as many parents do not voice their concerns about their childs sleeping habits unless asked. It is therefore vital for all physicians managing the paediatric population to be vigilant in screening for potential sleep problems in their patients. In particular, the physician should actively seek to identify sleep disorders in children presenting with behavioural/learning difficulties and in high-risk populations (eg, trisomy 21, attention deficit hyperactivity disorder). A screening tool that has been used widely to
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The childs bedroom should be conducive for sleeping at bedtime.
identify major sleep disorders in the paediatric population is the BEARS questionnaire. This comprises a set of parent- and child-directed questions which is age-appropriate (toddler/preschool, school-aged, and adolescence). The questions cover five major sleep domains: B = bedtime problems, E = excessive daytime sleepiness, A = awakenings during the night, R = regularity and duration of sleep, and S = snoring.1 In this article, we will discuss paediatric insomnias, sleep-related breathing disorders, circadian rhythm sleep disorders, and parasomnias.
INSOMNIAS IN CHILDHOOD
The term insomnia is a descriptive one and involves difficulty initiating or maintaining sleep. A child with insomnia can affect the sleep of not just the main caregiver but also the entire family. There are many causes of insomnia in children. They include behavioural insomnia of childhood and delayed sleep phase disorder, both of which are further discussed below. Medical conditions with nocturnal symptoms that disrupt sleep (eg, obstructive sleep apnoea [OSA], eczema, allergic rhinitis, asthma), psychological conditions (eg, stress, anxiety), or medications/stimulants (eg, b2 agonists, caffeine) can also cause insomnia.
Behavioural insomnia of childhood In behavioural insomnia of childhood, there are unique features characterized by the interplay of child temperament and maturity, parental style, and childparent interactions.
Sleep-onset Association Disorder
Sleep-onset association disorder is a condition characterized by reliance on specific stimulation, objects or conditions for initiating sleep or returning to sleep following an awakening.
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PA EDIA TRICS
Epidemiology. Onset is usually at 4 to 6 months old, and it has been estimated to affect 2550% of infants at 612 months old and 1520% of toddlers. 1 Presentation. It is normal for infants to wake intermittently in the night, but when they are unable to return to sleep without external factors like parental presence or rocking, recurrent or prolonged night awakenings can result. Persistent night
5
pletely till the next morning. Graduated extinction involves the parent responding to the child briefly, but after progressively longer periods of time to allow the child to fall back to sleep independently. This method is usually chosen in preference to the first because it is less emotionally taxing for both the child and parent. In fading, the parent physically distances himself/herself from the child each night, such that the eventual aim is to have the parent outside the childs room. Parentschild interaction is a very important influencing factor in a childs sleeping behaviour, and there is no one best method for every family. Any change would require consistency and perseverance of the caregiver(s) to work.
Limit-setting Sleep Disorder
awakenings can continue up to mid-childhood, but the negative sleep associations developed during infancy tend to taper off with age (eg, pacifier usage till 3 to 4 years old, parental help to fall asleep till 67 years old). Risk factors. Factors that may increase the likelihood of night awakenings include breastfeeding, co-sleeping, colic, intercurrent illness, parental anxiety, and when the child has achieved new motor/social milestones (eg, pulling to stand, separation anxiety). Management. The first step of management is to examine the details of the family set-up and bedtime habits, and to reinforce a strict bedtime and good sleep hygiene. The use of a transitional object like a blanket or stuffed toy can help to act as a positive sleep association and aid in selfsoothing. Self-soothing is a skill that usually develops beyond the age of 3 to 6 months old, but parents can help to encourage their babies to fall asleep independently early. They can put their babies down to bed drowsy but still awake so that he can learn to fall asleep on his own. Continuous patting of a child till he/she falls asleep or allowing him/her to fall asleep with a bottle in his mouth is also not advisable. Methods including extinction, graduated extinction, and fading have been used widely. Extinction involves the parent putting the child to bed at a fixed time and ignoring the childs cries com-
Limit-setting sleep disorder describes children who resist or refuse bedtime. Parents who are too lenient in enforcing a strict bedtime may encourage this behaviour. Epidemiology. Bedtime resistance has been found in up to a third of preschoolers. About 15% of children between 4 to 10 years old may still continue to have significant limit-setting sleep issues. Presentation. Bedtime refusal may manifest as refusal to go to bed or refusal to stay in bed. Attempts by the child to stall bedtime include screaming and crying, requesting for another drink of water, or bedtime story. Risk factors. In addition to over-lenient parenting, conflicting parental disciplinary styles, inconsistency in limit-setting (eg, allowing the child to fall asleep while watching television or spend some nights in the parents bed), and family tension can increase the occurrence of limit-setting disorder. Management. This includes good sleep practices mentioned earlier, and the importance of consistency in parental limit-setting cannot be
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Figure 2. Spectrum of sleep-disordered breathing.
Normal
Primary snoring
Upper airway resistance syndrome
OSA
No obstruction
Minimal/Partial upper airway obstruction
Maximal/Complete obstruction
emphasized more. The method of bedtime fading may be practised, in which the bedtime is gradually brought forward from the existing bedtime to the intended bedtime. Clear bedtime rules must be set, and positive reinforcement like rewards or star charts can help motivate children.
useful to demonstrate the habitually late sleep onset and late awakening. 6 Catch-up sleep on weekends should be documented as well. The main aim of management is to gradually adjust the sleep/wake schedule such that the typical school-going adolescent would still receive an adequate duration of sleep. Sleep hygiene must be reinforced. To reset the sleep rhythm earlier, it is important to get morning sunlight and avoid exposure to bright light late at night. Success has been shown to be largely dependent on patient and environmental factors (such as patient and parental motivation).
CIRCADIAN RHYTHM DISORDERS

Delayed Sleep Phase Disorder Epidemiology. Delayed sleep phase disorder is a disorder of timing that has been described in between 7% and 16% of adolescents and young adults.6 Presentation. Individuals with delayed sleep phase disorder go to bed much later than desired (eg, 4 am ) and find it very difficult to wake up in the morning. Daytime alertness decreases, and many teenagers report waking up tired and exhibit daytime somnolence,7 thus affecting school performance. Risk factors. Exactpathophysiological mechanisms remain largely unknown. Up to 40% of patients have a positive family history, and polymorphisms in the clock gene PER3 have been described.6 Management. Polysomnography is not routinely indicated unless there are symptoms suggestive of sleep-disordered breathing. Sleep logs are
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SLEEP-RELATED BREATHING DISORDERS

Sleep-related breathing disorders describe a spectrum of abnormalities in breathing patterns during sleep in which snoring is the predominant symptom. Primary snoring and OSA are at either ends of the continuum, and upper airway resistance syndrome falls in between (Figure 2).8
Primary Snoring Primary snoring is defined as snoring during sleep without associated apnoea, hypoventilation, hypoxaemia, or hypercarbia, and with no associated sleep disturbance or associated daytime symptoms.
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Upper Airway Resistance Syndrome Upper airway resistance syndrome is defined as partial upper airway obstruction sufficient to cause sleep disruption and daytime symptoms, but not gas exchange abnormalities. Obstructive Sleep Apnoea OSA is characterized by prolonged partial upper airway obstruction (obstructive hypoventilation) and/ or intermittent complete or partial obstruction (apnoea/hypopnoea) that disrupts normal ventilation during sleep and normal sleep patterns.9 Epidemiology. OSA is a condition that was once thought to be rare in the paediatric population in the 1970s, but newer studies have estimated the incidence to be 23% in children below the age of 10 years.10 There is a familial tendency, but the relative role of genetics versus environmental factors has yet to be determined. The peak age is between 4 to 7 years old, usually in children with enlarged tonsils and/or adenoids. With increasing rates of obesity in children, there is a second peak seen in older children above 8 years old. Causes. The most common aetiology of OSA is adenotonsillar hypertrophy. This group of children may have a typical adenoidal face, with a dull expression, allergic shiners, and mouth breathing. Obesity is another important cause of OSA in children. An adult study has shown that a 10% increase in body mass increases the subjects odds of developing moderate to severe OSA by sixfold.11 Risk factors. OSA tends to be worse during REM sleep as upper airway tone falls, allowing obstruction to manifest. Children with craniofacial syndromes like Pierre Robin sequence have fixed anatomical variations that predispose them to upper airway obstruction, while in children with neuromuscular disease like cerebral palsy, obstruction is caused by abnormal muscle tone. Children with
Table 2. Symptoms of obstructive sleep apnoea Sleep symptoms Snoring Apnoeas Snorting Gasping Paradoxical breathing Enuresis Restless sleep Frequent arousals Unusual body positions Wake symptoms Poor school performance Aggression Hyperactive behaviour Inattention Excessive daytime sleepiness Morning headaches
trisomy 21 or those with a positive family history of sleep problems also have higher risks of OSA. A severe upper respiratory tract infection or severe allergic rhinitis may produce transient OSA, especially in young children. Symptoms. Snoring is the most commonly reported symptom of OSA. However, as explained above, not all children with snoring have OSA. The converse is also true in that in some children with OSA, the history of snoring may not always be elicited. This may be due to the snoring being unnoticed because it occurs more during REM sleep, which predominates in the later half of the night, especially in a child who sleeps alone in his/her own room. In general, symptoms of OSA may be divided into night-time and daytime symptoms (Table 2). Complications. The impact of OSA is great, as recurrent obstruction leads to repeated desaturations, arousals, and sleep fragmentation.10 The secretion of growth hormone occurs during SWS and the consolidation of memory during REM sleep. If sleep is fragmented, a detrimental effect on growth and learning may arise. Cardiopulmonary complications (pulmonary hypertension, cor pulmonale) and metabolic conditions (insulin resistance, impaired
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glucose tolerance, hypertension) may arise if OSA is untreated or, rarely, even death can occur in severe untreated cases. Diagnosis. Snoring, mouth breathing, and daytime sleepiness often prompt parents to seek medical attention for their children. Clinical history and physical examination cannot always differentiate a primary snorer from a child with OSA. An overnight polysomnography is the gold standard test and involves continuous monitoring and recording of the childs sleep and breathing parameters. The aim is to look for sleep disruption, laboured breathing, airflow limitation or cessation, hypoxaemia, and hypercarbia.
PARASOMNIAS
Parasomnias are sleep-related phenomena that disrupt normal sleep and can take place during sleep wake transitions, NREM sleep, or REM sleep. As symptoms generally appear in early childhood and undergo spontaneous resolution, the aetiology has been proposed to be maturational in nature. 13 Parasomnias can generate great anxiety as some can be very bizarre and even violent, causing much distress to the caregivers.
Clinical history and physical examination cannot always differentiate a primary snorer from a child with OSA.
Treatment. In 2002, the American Academy of Pediatrics issued an evidence-based clinical practice guideline with recommendations for the management of OSA in children.
12
Confusional Arousals In a confusional arousal, the child may awake from typically SWS in the first third of the night or in the morning (on attempted awakening), frightened and crying. Epidemiology. The prevalence is estimated to be 515%, with the natural course being benign. The onset usually begins before 5 years of age, peaks during mid-childhood, and then undergoes spontaneous remission. Presentation. The child appears awake but is actually disorientated in time and space, and responds very poorly to commands and is slow in speech and mentation. He may sit up in bed and say words like no no no or go away! or even appear to be talking to an object. These episodes can last from a few minutes to a few hours with no recollection of the event thereafter. Somnambulism (Sleepwalking) Somnambulism has been described as partial arousal from sleep during SWS, and most occur during the initial third of the sleep period. Epidemiology. An estimated 1540% of all children will sleepwalk on at least one occasion, with only 34 % having frequent episodes that occur weekly to monthly. Peak age is usually between 4 to 8 years old. The majority settle by adolescence,
Adenotonsillectomy is curative in most children, and postoperatively, repeat polysomnograms may be done in some to document resolution. Continuous positive airway pressure is an option for those who are not surgical candidates or who respond poorly to surgery. Weight loss measures must be undertaken in those who are obese.
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and a significant familial pattern is associated. Sleepwalking can commonly co-occur with sleeptalking and night terrors.14 Presentation. Episodes often begin with sitting up in bed and looking around in a confused manner before ambulation. Routine behaviours like opening of the window or door and leaving the house can occur. Some may exhibit vocalization, but speech is usually meaningless and inappropriate. Children are usually difficult to wake during the episode and would appear confused and disorientated if awakened.
Key points
Night Terrors Night terrors also transpire during the SWS cycle, in the first third of sleep. Epidemiology. Typical onset is in early childhood between 2 to 4 years old, and spells are rare after adolescence.15,16 A familial pattern has been described, and more males than females are affected. Presentation. Episodes are sudden and are usually associated with intense autonomic arousal (like flushing, tachycardia, diaphoresis) and inconsolable screaming or crying. They are usually brief, lasting only a few minutes, and the child will return to sleep on his/her own. 17 The child will appear confused and disorientated if awakened. Factors that may increase the likelihood of occurrence of sleep terrors in susceptible children include periods of febrile illnesses, sleep deprivation (when naps are restricted or eliminated),18,19 or medications like antihistamines, stimulants and sedatives.20 Sleep terrors can usually be identified through information provided by parents but, in the rare, more complex cases, may warrant investigation with polysomnography or electroencephalography for seizure evaluation.21
Good-quality and adequate sleep for age is important for the well-being of a child, and health care professionals should include sleep screening as part of routine health care. Awareness and the practice of good sleep hygiene that is appropriate for age is important for the development and achievement of good sleep in children. Symptoms of obstructive sleep apnoea should be screened in all children, especially those with risk factors. Behavioural insomnia of childhood is the most common form of insomnia in children, but medical conditions and psychosocial issues should also be considered. Most parasomnias are benign and self-limiting, but may require further referral and investigations if severe or atypical in presentation.
Nightmare Disorders These attacks, as opposed to the conditions mentioned above, tend to occur in the last third of the night when REM sleep predominates. Epidemiology. Nightmares can occur in all ages but peaks in children between 6 to 10 years old. Nearly all children experience nightmares, and there is no clear familial pattern. Presentation. They are recurrent episodes of awakenings from REM sleep with recall of intensely disturbing dream mentation, usually involving fear or other intense emotions. Autonomic manifestations are usually mild, and vocalization is rare. Movements are also rare during nightmares because of normal REM sleep hypotonia. Trigger factors include sleep deprivation, stress, and traumatic events.14 Management of Parasomnias The arousal disorders are generally self-limiting, and the mainstay of management is conservative.
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Management is based on reassurance and education, with reinforcement of appropriate sleep hygiene. In cases in which there is potential danger (eg, unlocking of windows or doors in somnambulism), interventions should be in place to prevent injuries (eg, gates at the top of the stairway, padlocking of doors and windows, or an alarm bell on the doorknob of the childs room). Parents are advised not to wake the child up during episodes, but to gently guide them back to bed. When the events are predictably recurrent, scheduled awakening just before the typical time of the episode on a nightly basis for a few weeks has been shown to be effective. Pharmacotherapy has been used rarely and would first require consultation with a sleep specialist and detailed counselling of the parents.
CONCLUSION
Paediatric sleep is an area of growing interest, and there is an increasing awareness of the need for good sleep in children. Different sleep disorders are prevalent in the different age groups, but for all children, poor/insufficient sleep and sleep-disordered breathing can have mild to serious sequelae. Screening for sleep disorders for all children should be part of routine health care, with onward referral to a paediatric sleep specialist for symptomatic, complex, or high-risk patients.
About the Authors

Dr Wong is Registrar, Dr Teoh is Head and Consultant, and Professor Chay is Senior Consultant in the Respiratory Medicine Service, Department of Paediatric Medicine, KK Womens and Childrens Hospital, Singapore.
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. Mindell JA, Owens JA. A Clinical Guide to Pediatric Sleep: Diagnosis and Management of Sleep Problems. Philadelphia, PA: Lippincott Williams &Wilkins; 2003. 2. Owens JA, Palermo TM, Rosen CL. Overview of current management of sleep disturbances in children, II: behavioural interventions. Curr Ther Res Clin Exp 2002;63(Suppl B):B38B52. 3. Mindell JA. Sleep disorders in children. Health Psychol 1993;12:151162. 4. Owens JA, Spirito A, McGuinn M, Nobile C. Sleep habits and sleep disturbances in elementary school-aged children. J Dev Behav Pediatr 2000;21:2736. 5. Mindell JA, Owens JA. A Clinical Guide to Pediatric Sleep: Diagnosis and Management of Sleep Problems. Philadelphia: Lippincott Williams & Wilkins; 2003. 6. Anders TF, Halpern LF, Hua J. Sleeping through the night: a developmental perspective. Pediatrics 1992;90:554560. 7. Bhargava S. Diagnosis and management of common sleep problems in children. Pediatr Rev 2011;32:9198. 8. Glaze DG. Childhood insomnia: why Chris cant sleep. Pediatr Clin North Am 2004;51:33 50. 9. Spicuzza L, Leonardi S, La Rosa M. Pediatric sleep apnea: early onset of the syndrome? Sleep Med Rev 2009;13:111122. 10. American Thoracic Society. Standards and indications for cardiopulmonary sleep studies in children. Am J Respir Crit Care Med 1996;153:866878. 11. Urquhart D, Montague ML. When to remove tonsils and the alternatives. Paediatrics & Child Health 2012;22:3741. 12. Peppard, PE, Young,T, Palta, M et al. Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA 2000;284:30153021. 13. American Academy of Pediatrics. Clinical practice guideline: diagnosis and management of childhood obstructive sleep apnoea syndrome. Pediatrics 2002;109:704712. 14. Sheldon SH. Parasomnias in childhood. Pediatr Clin North Am 2004;51:6988. 15. Lim LL, Tang J; Singapore Sleep Society. Sleep Medicine: A Clinical Guide to Common Sleep Disorders. Singapore: CMP Medica Asia; 2008. 16. Laberge L, Tremblay RE, Vitaro F, Montplaisir J. Development of parasomnias from childhood to early adolescence. Pediatrics 2000;106:6774. 17. Chokroverty S, Hening WA, Walters AS. An approach to the patient with movement disorders during sleep. In: Chokroverty S, Hening WA, Walters AS, eds. Sleep and Movement Disorders. Philadelphia: Butterworth Heinemann; 2003:265272. 18. Rosen G, Mahowald MW, Ferber R. Sleepwalking, confusional arousal, and sleep terror in the child. In: Ferber R, Kryger M, eds. Principles and Practice of Sleep Medicine in the Child. Philadelphia: WB Saunders; 1995:99106. 19. Kales JD, Kales A, Soldatos CR, Chamberlin K, Martin ED. Sleepwalking and night terrors related to febrile illness. Am J Psychiatr 1979;136:12141215. 20. Owens JA, Millman RP, Spirito A. Sleep terrors in a 5-year-old girl. Arch Pediatr Adolesc Med 1999;153:309312. 21. Mahowald MW. Arousal and sleep-wake transition parasomnias. In: Lee-Chiong TL, Sateia MJ, Carskadon MA, eds. Sleep Medicine. Philadelphia: Hanley & Belfus; 2002:207213. 22. Guilleminault C, Palombini L, Pelayo R, Chervin RD. Sleepwalking and sleep terrors in prepubertal children: what triggers them? Pediatrics 2003;111:e17 e25.
OBSTETRICS OBSTETRICS
II
Perinatal Case Management Bleedingas Disorders Caring for Mothers They Care in Pregnancy for Babies
Eleftheria Lefkou, MD, PHD; Beverley J Hunt, MB, FRCP, FRCPath, MD Chng Ying Chia, MA (Applied Social Studies); Jemie Biwen Wang, Bachelor of Psychology (Hons); Helen Chen, MBBS, M Med (Psych), Dip. Psychotherapy
INTRODUCTION
Haemostasis aims to keep blood flowing normally and yet paradoxically has to form a clot quickly to restrict excessive bleeding from blood vessels when they are damaged. Owing to these two opposing aims, the haemostatic system is necessarily complex. Table 1 provides an aetiological division of bleeding disorders. Pregnancy results in increment of levels of fibrinogen, factors VII, VIII, IX, X and XII and von Willebrand factor (vWF), and decreased levels of factor XI and protein S, all of which lead to a prothrombotic state. Thus, most inherited bleeding disorders tend to improve during pregnancy but worsen immediately afterwards as the haemostatic system reverts quickly to the non-pregnant state. An altered fibrinolytic state is part of a normal physiological response to pregnancy due to an increase in the fibrinolytic inhibitors PAI1 and PAI-2 and tissue plasminogen activator. We review the management of bleeding disorders in pregnancy and the puerperium. The first part covers thrombocytopenia, the second the thrombotic microangiopathies, and the last part the commonest inherited bleeding disorders and acquired haemophilia.
THROMBOCYTOPENIA IN PREGNANCY
Thrombocytopenia is a common finding in pregnancy, occurring in 710% of pregnancies (Table 2). The most common causes are gestational thrombocytopenia (GT) (75%), 1520% are due to thrombotic microangiopathies when secondary to hypertensive disorders, 34% due to immune causes (3%) and other rare causes include constitutional thrombocytopenias, infection and malignancy (< 1%).
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Table 1. Bleeding disorders
Platelets Thrombocytopenia Failure of production
Increased destruction
Pregnancy directly related
Dilutional/uncertain Platelet dysfunction Hereditary
Decreased megakaryocyte mass radiation, chemicals, drugs; intrinsic bone marrow abnormalities (aplastic anaemia, leukaemia, myelofibrosis, myelodysplastic syndrome, etc); replacement of bone marrow with carcinoma cells (plasma cells, etc) Ineffective thrombopoiesis megaloblastic anaemias (B12, folic acid deficiency) Immune mechanisms: autoimmune thrombocytopenic purpura; autoimmune diseases (lupus erythematosus) Splenomegaly (usually secondary to liver disease) Microangiopathies (pre-eclampsia, HELLP, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura) Acute fatty liver Gestational thrombocytopenia Human immunodeficiency virus Disorders of platelet adhesion (BernardSoulier syndrome) Disorders of platelet aggregation (thromboasthenia, Glanzmann) Disorders of platelet secretion (a granule deficiency Grey platelet syndrome, dense granule deficiency delta storage pool deficiency, aspirin-like disorders) Disorders of platelet procoagulant activity (Scott syndrome) Drugs aspirin and other non-steroidal anti-inflammatory drugs; alcohol, antibiotics (carbenicillin, penicillin, moxalactam, third-generation cephalosporins) Other uraemia, liver disease, heart bypass surgery, haematological malignancies, myeloproliferative disorders, leukaemia, etc
Acquired
Vessel wall Drugs (chronic glucocorticoid use, penicillins, sulphonamides) Vitamin C deficiency Paraproteinaemia HenochSchnlein purpura and other vasculitis Hereditary defects Coagulation Acquired causes
Hereditary haemorrhagic telangiectasia EhlersDanlos syndrome Vitamin K antagonism/deficiency Liver disease Anticoagulation therapy Disseminated intravascular coagulation Factor inhibitors Factor deficiencies (von Willebrand disease, haemophilia A and B, rare FXI, FVII, FX, prothrombin deficiency, fibrinogen deficiency/dysfunction)
Inherited causes
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Gestational Thrombocytopenia The platelet count in pregnancy is lower than the non-pregnant state. In 58% of all pregnancies, the platelet count at term is below the normal range (150400 10 9/L). In GT, platelet counts are typically > 70 109/L, with about two-thirds just below the normal lower limit, eg, between 130 10 9/L and 150 109/L. It is exceptional for the platelet count to fall below 80 109/L, but in rare cases, subsequently confirmed as GT, counts may be as low as 50 10 9/L. The aetiology remains uncertain, but at least part represents a dilutional effect of platelet mass due to the expanded plasma volume of pregnancy and possibly accelerated destruction of platelets when passing over trophoblasts. Characteristically: GT is mild and asymptomatic There is no past non-pregnant medical history of thrombocytopenia in the mother It occurs late in pregnancy (second trimester, more pronounced at labour) There is no fetal thrombocytopenia There is no association with maternal or neo natal haemorrhage It resolves spontaneously after delivery (within 7 days to 6 weeks postpartum) Bleeding times are normal, unless platelet count falls below 80 109/L. It should be remembered that fibrinogen, while being the end point of the coagulation cascade and thus directly responsible for fibrin production, is also the ligand for platelet aggregation. Thus, the increase in fibrinogen levels of pregnancy allows pregnant women to tolerate lower platelet levels than non-pregnant women. Immune Thrombocytopenic Purpura Immune thrombocytopenic purpura (ITP) is due to the formation of autoantibodies, usually IgG,
Table 2. Causes of thrombocytopenia in pregnancy Pregnancy-related Gestational (or incidental, 75%) Pre-eclampsia Other Spurious (EDTA-induced platelet aggregation) send a citrate sample to exclude this Autoimmune (immune thrombocytopenic purpura, drug-induced, systemic lupus erythematosus, antiphospholipid syndrome) Viral, eg, human immunodeficiency virus, Epstein-Barr virus, cytomegalovirus, von Willebrand type IIB disease Haemolytic uraemic syndrome/ thrombotic thrombocytopenic purpura Congenital/marrow disease/hypersplenism/liver disease Drugs (not low-molecular-weight heparins)
Haemolysis, elevated liver enzymes and low platelet (HELLP syndrome) Disseminated intravascular coagulation Acute fatty liver Folate deficiency
against platelet surface glycoproteins, especially IbIX and IIbIIIa, causing their premature destruction by the reticuloendothelial system. ITP is common in haematology practice, with an incidence in the general adult population of 6.6 per 100,000, with 15 cases per 10,000 pregnancies. However, it is around 100 times less common than GT in pregnancy. The majority of cases occur alone, but rarely it can be associated with systemic lupus erythematosus and human immunodeficiency virus, or is secondary to drugs. Due to the increased platelet turnover, the residual platelets are young and more haemostatically active; therefore, the patients rarely bleed and cerebral haemorrhage occurs in less than 1%. In the last 30 years, no maternal deaths due to ITP have
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Table 3. Distinguishing immune thrombocytopenic purpura (ITP) from gestational thrombocytopenia (GT)
thy or autoimmune disease. Bone marrow examination is unnecessary unless there is suspicion of leukaemia or lymphoma. The routine measurement of platelet antibodies is not recommended because the results are not sufficiently sensitive or specific. The aim of management is to maintain a safe platelet count. Antenatally, platelet counts > 2030 10 9/L do not need treatment until the third trimester unless there is also a defect in platelet function or abnormal coagulation. Routine platelet counting may underestimate the total count, for most analyzers count platelets according to a size range. However, young platelets may be very large and have the size of red cells, and therefore are counted as such. If there is doubt, some centres have immune
GT Time of presentation Platelet count Neonatal thrombocytopenia Platelet size > Second trimester > 7080 109 No
ITP From first trimester More severe Possible No/yes Normal/big No/yes
Resolution after delivery Yes Normal Antiplatelet antibodies No/yes
been reported, and maternal morbidity is minimal platelet counting based on light scatter. if appropriate therapy is administered during pregnancy and childbirth. From 35 to 36 weeks, it is usual to give treatment to raise the platelet count to at least 50
Usually the clinical problem is differentiating 10 9/L for normal vaginal delivery and caesarean GT from ITP (Table 3). This has minor clinical impor- section. Concerns over the risk of haematoma fortance for the mother but is essential for the fetus mation and neurological damage have led to rec owing to the transplacental passage of antibody, ommendations that spinal or epidural anaesthesia ITP may rarely cause thrombocytopenia in the fetus; not be performed unless the platelet count is > 80 GT does not. Neonatal thrombocytopenia occurs in 109/L. This recommendation is based on consenup to 14% of pregnancies complicated by ITP: 7.5% sus rather than evidence. Thromboelastogram data have severe thrombocytopenia with platelet counts would suggest that lower levels of thrombocytope< 50 109/L, although only 4% have platelet counts nia might be tolerated. There is no evidence that < 20 109/L, and are therefore at risk for haemor- the bleeding time predicts the risk of haemorrhage rhage at birth. Splenectomy prior to pregnancy is in this situation. the only recognized risk factor associated with the Current recommendations for the mode of development of neonatal thrombocytopenia. This delivery do not support caesarean section being a may be due to the fact that splenectomized women safer option for the fetus, except for obstetric indiusually have more severe ITP and large amounts of cations. The use of vacuum extraction and complicirculating autoantibodies. The main concern for cated instrumental delivery is contraindicated, as the newborn during the labour is trauma-provoking are the use of scalp electrodes for monitoring the neonatal cerebral haemorrhage. The British Society of Haematology recommends that all women with platelet counts less Specific Treatments for ITP than 100 10 9/L should be screened for clinical or The main treatment options for maternal ITP are laboratory evidence of pre-eclampsia, coagulopa- corticosteroids or intravenous immunoglobulin
labour.
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Gestational thrombocytopenia does not require treatment in pregnancy and resolves spontaneously after delivery.
(IVIg). Vinca alkaloids, androgens and most immunosuppressive drugs should not be used in pregnancy, however azathioprine is safe. Steroids. The British Society of Haematology guidelines recommend 1 mg/kg but in our experience a dosage of 1020 mg may be effective in increasing a platelet count of < 50 to levels > 80 109/L. Doses of prednisolone less than 20 mg a day are metabolized in the placenta, higher doses to the mother increase the risk of premature rupture of the membranes, adrenal suppression in the fetus and a small increase of cleft lip if used in the first trimes-
international shortage of IVIg preparations. Anti-D. This is given to rhesus-positive patients in whom red cells coated in antibody block the reticuloendothelial system, preventing platelet destruction. It is currently unavailable in the UK, and experience in pregnancy has been limited. Some studies have administered intravenous anti-D daily for 5 days; others a single dose lasting < 5 minutes. In a trial, eight women were treated in the second and third trimester with one to seven anti-D infusions. The response rate was 75%, with a fall of haemoglobin of > 2 g/dL in one patient. Anti-D crosses the placenta, but only three of the seven rhesus-positive babies were Coombs test (antibody present on red cells) positive; however, none of them was anaemic. Splenectomy. This, including the laparoscopic approach, is considered acceptable for patients with refractory ITP and severe bleeding. IdealJPOG JAN/FEB 2013 19
ter. prescription, 0.4 mg/kg/d for 35 days) has a similar response rate as in the non-pregnant woman; however, duration of response is short, usually lasting 23 weeks, and repeated infusions may be required. Currently, there is an
Intravenous immunoglobulin. IVIg (usual
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ly, this should be performed in the second tri-
The foreign fetal platelet antigens are inherited from the father. The majority of cases are caused by (HPA)-1a (incidence, 80%) and HPA-5b (15%), but rarer reactions have been reported. The incidence of NAIT is reported to be 1 in 1,100 live births, but it may be underdiagnosed. Mortality is around 10% of presenting cases, with neurological sequelae, including intracranial haemorrhage (ICH), and subsequent neurodevelopmental delay in up to 25%. NAIT should be particularly suspected from the history if there has been a previously affected sibling or recurrent fetal loss. Clinical presentation could be with antenatal fetal ICH/hydrocephalus, premature labour, bruising or bleeding in the neonate, excessive haematoma at injection sites, and postnatal ICH. NAIT should be diagnosed after the exclusion of sepsis, necrotizing enterocolitis, disseminated intravascular coagulation (DIC), placental insufficiency, congenital infection, asphyxia, and artefact. Samples of the mothers and newborns blood should be sent to the Blood Transfusion Laboratory to look for antiplatelet antibodies. Definitive diagnosis of NAIT depends on testing for parental platelet antigens. The risk of a subsequent pregnancy being affected is 100% if the father is homozygous for the reacting antigen and 50% if heterozygous. In general, subsequent pregnancies are at least as severely affected as the first. It is now also possible to obtain fetal DNA from maternal blood and to platelet-antigen type the fetus early in pregnancy to assess whether the fetus of heterozygous father is affected. Antenatal therapy in subsequent pregnancies remains contentious, but in affected fetuses options include intrauterine platelet transfusion, maternal immunoglobulin and steroids, all of which should be done at a specialized fetal medicine centre.
mester. ractory ITP may respond to high-dose intravenous methyl prednisolone and intravenous IVIg. This needs to be managed by an expert.
{{
Life-threatening bleeding in a severe ref- antibodies directed against human platelet antigen
Rituximab. There is limited data about the use of CD20 monoclonal antibody in pregnancy. The manufacturers recommend abstaining from pregnancy during and for 12 months after its use. Rituximab crosses the placenta and may cause a delay in neonatal B-lympho cyte maturation, which seems to normalize post partum.
{{
Thrombopoietin receptoragonists. These are not licensed for use in pregnancy, and animal studies have shown evidence of fetal abnormality. The manufacturers of both eltrombopag and romiplostim have set up registries to collect data on their use in human pregnancies. There are no data on the excretion of these drugs in breast milk.
Type IIB von Willebrand Disease and Thrombocytopenia Type IIB von Willebrand disease (vWD) should be considered in the differential diagnosis of thrombocytopenia developing during pregnancy. The recognition of this syndrome is important because of the different and difficult clinical management problems associated with it (see below). Neonatal Allo-immune Thrombocytopenia Neonatal allo-immune thrombocytopenia (NAIT) is a disorder caused by feto-maternal platelet incompatibility, analogous to that in rhesus haemolytic disease, with maternal antiplatelet IgG antibodies crossing the placenta and destroying fetal platelets.
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If the newborns platelet count is < 30 109/L and the maternal count is normal, the treatment of choice is urgent transfusion of 10 mL/kg of matched platelets. In the majority of cases, these will be HPA-1a-negative, but Maori and Asian mothers often have antibodies other than anti-HPA-1a. If antigen-negative platelets are not available, IVIg 1 g/kg/d for 2 days may be effective. There is often a delay in response of 2448 hours, leaving a window of risk for ICH.
that of pre-eclampsia with severe liver involvement, which may result in areas of hepatic necrosis. The diagnosis is made by finding red cell fragmentation on the blood film, low platelets, and abnormal liver function tests. DIC may occur in the more severe cases. The recent finding that mutations in regulation of the complement genes are associated with HELLP is of interest. This is a progressive condition, and the only certain therapeutic measure is prompt delivery; in the majority of cases, women have complete recovery within 2448 hours after labour, although some may worsen after delivery and/or continue to have symptoms for up to 14 days. HELLP is associated with a 36% incidence of acute renal failure, 17% placental abruption, and associated risks of intrauterine death and low birthweights. Steroids and plasma exchange have been used anecdotally with variable results. HELLP syndrome should be distinguished from acute fatty liver of pregnancy, a rare condition also associated with thrombocytopenia but not microangiopathic haemolytic anaemia. Clinical presentation of acute fatty liver of pregnancy is similar to HELLP, almost always occurring in the third trimester. The management is delivery followed by supportive, often intensive, therapy.
THROMBOTIC MICROANGIOPATHIES
A thrombotic microangiopathy occurs when there is thrombocytopenia and also red cell fragments are found in a blood film. The red cell fragmentation occurs when the red cells pass over fibrin in the microvasculature. Key investigations are a full blood count, blood film, and coagulation screen. A spectrum of thrombotic microangiopathies exists in pregnancy and commonly are due to the hypertensive disorders of pregnancy, as described below.
Pre-eclampsia and HELLP Syndrome Thrombocytopenia occurs in up to 50% of women with pre-eclampsia (PET), and the severity parallels the severity of PET. Thrombocytopenia due to PET should be managed according to the general guidelines for thrombocytopenia described above. HELLP syndrome is a variant of pre-eclampsia occurring in the second or third trimester of pregnancy, and presents occasionally post partum. It complicates between 0.5% and 1% of pregnancies and 1020% of those with PET, and is associated with high maternal morbidity and mortality. The clinical presentation is usually antenatal in 70%, the rest peripartum. The usual presentation is with upper abdominal pain, nausea, vomiting, headache, and visual disturbances. The pathophysiology is
Disseminated Intravascular Coagulation Disseminated intravascular coagulation is a clinicopathological syndrome characterized by an uncontrolled systemic activation of coagulation leading to microvascular deposition of fibrin, and thus to consumption of coagulation factors, platelets, and physiological anticoagulants. This produces a reduction in platelet count and in coagulation factors, especially fibrinogen, and so prolongation of the activated partial thromboplastin time and international normalized ratio. Obstetric causes of DIC include amniotic fluid
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embolism, placental abruption, eclampsia or preeclampsia, retained dead fetus, and septic abortion. Sepsis is one of the major causes of DIC in pregnancy. The major obstetric causes of sepsis are septic abortion, intra-amniotic infection and postpartum endometritis. In placental abruption, the degree of placental separation correlates with the extent of DIC. Fortunately, the DIC in this situation is usually short-lived and self-limiting. The pathogenic mechanism of DIC is usually the leakage of tissue factorlike material into the circulation, with the consequent systemic activation of coagulation. However in amniotic fluid embolism, there is a coagulopathy-due direct activation of FX by the amniotic fluid; this is associated with cardiovascular collapse due to an allergic response to amniotic fluid. Management of DIC involves treating the cause and replacing the missing haemostatic components with blood products. Rarely, chronic DIC requires low-dose anticoagulation to switch off the stimulus to DIC, and the advice of an expert in haemostasis should be sought.
renal impairments are present in only a minority of patients. It is due to a deficiency of ADAMTS-13; without this protein, spontaneous platelet aggregates can occur in the microvascular. Deficiency can be inherited or acquired, the latter usually due to an autoantibody. Human immunodeficiency virus is an increasingly recognized cause. In pregnancy, about a third of cases are due to a late presentation of previously undiagnosed congenital TTP. The distinction of TTP from pregnancy-related complications pre-eclampsia, eclampsia and HELLP syndrome may be difficult. TTP is more common in women than in men, with 1225% of cases diagnosed during pregnancy or post partum, with 75% of episodes occurring around the time of delivery. Routine investigations at presentation should include full blood count, film, clotting screen, lactate dehydrogenase, direct antiglobulin test, urea and electrolytes, liver function tests, and urine dipstick for protein.
Thrombotic Thrombocytopenic Purpura Thrombotic thrombocytopenic purpura (TTP) is an acute, rare and life-threatening disorder affecting 37 persons per million per annum. TTP is a clinical diagnosis, characterized by the classic pentad of thrombocytopenia, microangiopathic haemolytic anaemia, fluctuating neurological signs, renal impairment, and fever, often with insidious onset. Neurological impairment has multiple manifestations including headache, bizarre behaviour, transient sensorimotor deficits, seizure, and coma. Additional complications that may be seen include gastrointestinal ischaemia (manifest as abdominal pain) and serous retinal detachment. However, some TTP patients do not have neurological symptoms or signs at presentation, and fever and
The distinction of TTP from pregnancy-related complications pre-eclampsia, eclampsia and HELLP syndrome may be difficult
The management of acute TTP is with immediate plasma exchange and general supportive therapy, including red cell exchange. Immediate treatment is required, for delay can result in death due to platelet aggregates causing myocardial infarc-
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tion, such deaths account for 1% of the UK maternal mortality. The British Society for Haematology TTP guidelines recommend urgent plasma exchange in any thrombotic microangiopathy that cannot be explained by a non-TTP pregnancy-related cause. They advise that women with known congenital TTP should attend specialist centres and receive ADAMTS-13 supplementation during the pregnancy and puerperium, and have serial monitoring of fetal wellbeing.
Haemolytic Uraemic Syndrome Haemolytic uraemic syndrome (HUS) is thrombotic microangiopathy characterized by microangiopathic haemolytic anaemia, thrombocytopenia, and renal involvement. HUS is described either as D (diarrhoea)-positive HUS, which most commonly presents in children and is associated with the release into the circulation of Shiga-like toxin after an infection by Escherichia coli (O157:H7); or atypical, usually due to dysregulation of complement. Postpartum HUS is a very rare atypical HUS, and complement abnormalities have been detected in 90% of cases in one series. There is poor response to plasma exchange, but eculizumab, a terminal complement inhibitor, appears to be a promising agent for atypical HUS.
INHERITED COAGULATION FACTOR DEFICIENCIES

In general, in those with inherited bleeding disorders, intramuscular injections, invasive monitoring techniques, vacuum extraction and rotational/midcavity forceps should be avoided for the benefit of mother and baby, and a cord blood sample should be sent to assess fetal levels of the deficient factor. Vitamin K should be given orally to the newborn, and routine immunizations should be given intradermally or subcutaneously.
von Willebrand Disease von Willebrand disease is the most common inherited bleeding disorder, affecting 13% of the general population and 13% of women with menorrhagia. vWF is a large multimeric glycoprotein, which acts as a ligand molecule for normal platelet adhesion and aggregation, and also carries factor VIII, increasing factor VIIIs half-life fivefold. There are three main types of vWD (types I, II and III), and within type II there are four subtypes (A, B, M and N). In type I, the commonest (75%), there is a quantitative decrease in vWF levels. Type II (2025%) is a qualitative disorder. Type IIB, a special qualitative variant of vWD, accounts for < 5% of all patients with vWD; it is characterized by the selective loss of high-molecular-weight vWF multimers in plasma owing to their abnormally increased reactivity with platelets. Both types I and II are inherited as autosomal dominant traits. Type III, the most severe and the rarest form (< 0.01% of the general population and < 5% of vWD cases), is inherited as an autosomal recessive trait. The typical clinical presentation of women with vWD is easy bruising, prolonged bleeding from mucous membranes, especially menorrhagia, bleeding after surgery and dental extraction, and a family history. However, many women with mild vWD remain undiagnosed within the community. Questions about near relatives bleeding history, especially at the time of surgery, dentistry and childbirth, are essential in history taking. One of the effects of pregnancy is to increase levels of vWF, so mothers with type I vWD will not bleed antenatally. However, levels of vWF fall precipitously post partum, resulting in an increased risk of bleeding. The clinical presentation of type IIB vWD is characteristically worsening thrombocytopenia during pregnancy and after the administration of desmopressin. Thrombocytopenia in type IIB vWD is thought to be due to enhanced affinity of the abJPOG JAN/FEB 2013 23
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Table 4. Severity of haemophilia and clinical presentation
tive delivery. In type III vWD, all types of delivery require treatment. All women with vWF activity < 50 IU/dL should receive prophylactic treatment prior to the onset of labour or planned caesarean section. Regional anaesthesia can be offered when vWF activity is > 50 IU/dL. Active management of the third stage should be practised. Postdelivery vWF levels should be monitored, and prophylaxis should be given to maintain vWF
Severe < 1% FVIII Moderate 25% FVIII Mild 540% FVIII
Bleed spontaneously into joints and cavities Bruise badly and bleed +++ after surgery Bruise badly and bleed +++ after surgery
normal vWF for the patients platelet vWF receptor, the glycoprotein IbIX complex. This leads to subsequent platelet activation, aggregate formation, and clearance by the reticuloendothelial system. A possible explanation for the presentation of thrombocytopenia during pregnancy is that type IIB represents a variant, and these women become thrombocytopenic only during periods of increased production of the abnormal vWF, brought about by the physiological stimulus of pregnancy. Diagnosis is made by performing platelet aggregation with low ristocetin concentration, and multimeric analysis will show absence of high-molecular-weight forms. In type III vWF levels show little increment in pregnancy, and these women require vWF concentrates. Desmopressin is of no value in these patients. In women with type I vWD, functional and antigenic test for factor levels (vWF antigen, vWF activity and FVIII:C) should be checked at booking, 28 and 34 weeks gestation and prior to invasive procedures. Prophylactic treatment should be given when factors are < 50 IU/dL to cover invasive procedures and delivery. Desmopressin also can be used. Tranexamic acid can also be used for prevention or control of haemorrhage at delivery. The combined oral contraceptive pill increases levels of vWF and so can be used post partum. Women with type I vWD generally do not require prophylactic treatment for delivery. In women with type II vWD, treatment is required for operaJPOG JAN/FEB 2013 24
activity and FVIII levels > 50 IU/dL for at least 3 days (5 days in caesarean section). Tranexamic acid and the combined oral contraceptive should be considered in the case of postpartum haemorrhage.
Haemophilias Haemophilia A (factor VIII deficiency) and B (factor IX deficiency) are X-linked recessive disorders, and affect approximately 1 in 10,000 male births. At least 30% of newly diagnosed cases of haemophilia occur as a consequence of a new mutation, affecting either the male propositus or a female carrier in whom there may be no personal history of bleeding problems, and so prenatal awareness of all neonates with haemophilia is not possible. In each pregnancy of a mother carrier of haemophilia, there is a 50% chance of having an affected son and a 50% chance of having a daughter who will also be a carrier of the disease. Haemophilia is divided clinically into mild, moderate, and severe, and the clinical presentation depends on severity (Table 4). Clinical presentation of severe haemophilia (less than 1% factor VIII) is with spontaneous haemarthrosis and bleeding into cavities. Women can be carriers, and they usually do not have serious bleeding problems unless they have severe lyonization. The United Kingdom Haemophilia Centre Doctors Organisation recommends that haemophilia carriers should have their factor level checked at booking and at 28 and 34 weeks gestation to al-
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low appropriate management of labour and delivery and to assess the need for prophylactic treatment, although supplementation is uncommonly required.
may be considered on an individual basis, taking into account knowledge of the fetal haemophilia status and potential maternal morbidity. Ventouse extraction, rotational and midcavity forceps are associated with an increased risk of bleeding and should be avoided. Invasive monitoring procedures such as placement of intrapartum scalp electrodes and fetal scalp blood sampling should be avoided, and active management of the third stage should be practised in carriers of haemophilia. Factor levels should be monitored post delivery and maintained > 50 IU/dL for at least 3 days (5 days in caesarean section). During labour, recombinant FVIII and FIX is the
Haemophilia carrier status itself is not a contraindication to vaginal delivery
In known or suspected cases of mothers who are haemophilia carriers, there should be adequate provision for genetic screening and counselling, which ideally should be completed pre-pregnancy. Pre-implantation genetic diagnosis may be considered by some couples in preference to conventional invasive prenatal diagnosis by chorionic villous sampling. In a pregnancy where the mother is a confirmed or suspected carrier of haemophilia A or B, fetal sexing should be performed as part of antenatal care as this will be helpful in managing pregnancy and delivery. Fetal sexing can be performed either by ultrasound examination at 1820 weeks gestation or, ideally, by testing circulating cell-free fetal DNA from maternal blood for Y chromosome specific sequences from the seventh week of gestation. For women wishing to avoid the miscarriage risk associated with first-trimester prenatal diagnosis, but who do wish information, which would influence their intrapartum management, there is an option for third-trimester amniocentesis, with a 1% risk of causing preterm labour. Regarding the mode of delivery, haemophilia carrier status itself is not a contraindication to vaginal delivery. The option of elective caesarean section in an attempt to reduce the risk of neonatal ICH
recommended treatment of choice in pregnant carriers of haemophilia A and B when factor levels are < 50 IU/dL. Desmopressin increases plasma levels of vWF and FVIII and thus is potentially effective in carriers of haemophilia A (but not B). The efficacy and safety of desmopressin in pregnancy have not been systematically studied, but potential side effects, including placental insufficiency, miscarriage or preterm labour, and maternal and/or fetal hyponatraemia, are rare. Desmopressin does not pass into breast milk in significant amount. Regional anaesthesia in carriers of haemophilia is not contraindicated if the coagulation screen is normal and the relevant factor level is above 50 IU dL (or raised to > 50 IU dL by prophylactic treatment). It should be performed by an expert anaesthetist with the help of a specialized haematologist for assessment of coagulation status and arrangement of treatment if required.
Factor XI Deficiency FXI deficiency is an autosomal disease that affects 1 in 100,000 people, most frequently among the Ashkenazi Jewish population where there is an incidence of 8%. Homozygotes are severely affected with FXI levels of < 15 IU/dL while heterozygotes
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Practice points
68 hourly should be considered post delivery and for 3 days post partum, or 5 days following caesarean section. FXI concentrates carry a thrombotic
Gestational thrombocytopenia does not require treatment in pregnancy, is not associated with neonatal thrombocytopenia, and resolves spontaneously after delivery Women with immune thrombocytopenic purpura, which is much rare than gestational thrombocytopenia, can tolerate lower platelet levels in pregnancy, and intervention is only needed in preparation for delivery if the platelet counts fall below 5080 109/L In women with mild von Willebrand disease (vWD), the response to pregnancy, specifically increased levels of von Willebrand factor and FVIII, may mean there is no need for treatment Type II B vWD may present with a gradually falling platelet count during pregnancy, and in such patients enquiry should be made about a personal and family history of bleeding All pregnant women with known inherited bleeding disorders should be managed jointly with a haemophilia centre If obstetric haemorrhage continues longer than expected and no bleeding point can be found, then vWD should be considered, and haematological advice sought urgently
risk, and so peak levels should not exceed 70 IU/ dL. More recently, recombinant FVIIa has been used successfully in FXI deficiency.
have partial deficiency with levels of 1570 IU/dL (normal range, 70150 IU/dL). In FXI deficiency, factor levels do not reflect the severity of bleeding, bleeding is inconsistent within a family, and the clinical presentation is variable. Haemorrhage tends to occur in sites prone to fibrinolysis; thus, women with partial or severe deficiency are at risk of excessive uterine bleeding. The unpredictable nature of FXI deficiency requires close monitoring and specialized and individualized joint care with the haemophilia centre during pregnancy and the puerperium. Levels of FXI should be checked at booking, 28 and 34 weeks gestation, and prior to invasive procedures. In general, women with FXI levels < 15 IU/ dL have a 1630% risk of excessive bleeding during delivery, and should receive prophylactic FXI concentrate at the onset of labour or prior to planned induction or caesarean section. Tranexamic acid 1 g
Inherited Disorders of Fibrinogen Genetic abnormalities of fibrinogen comprise quantitative abnormalities (afibrinogenaemia and hypofibrinogenaemia) and qualitative abnormalities (dysfibrinogenaemia and hypodysfibrinogenaemia). Afibrinogenaemia is a rare disorder (affecting 12 per million). Fibrinogen levels are < 0.1 g/L, and bleeding manifestations range from mild to severe. Frequently, umbilical cord haemorrhage is the first presentation. Other bleeding manifestations include epistaxis and oral mucosal bleeding, haemarthrosis and muscle haematoma, gastrointestinal bleeding, menorrhagia, postpartum haemorrhage, bleeding after surgery and trauma, spontaneous splenic rupture and, very rarely, ICH. Recurrent spontaneous first-trimester loss is common because adequate plasma fibrinogen is vital for implantation. Patients with hypofibrinogenaemia tend to have mild bleeding following trauma and surgery. Those with dysfibrinogenaemia have bleeding (28%) or thrombosis (20%), with some first-trimester losses, but the majority are asymptomatic (62%). The management of bleeding episodes in afibrinogenaemia or dysfibrinogenaemic patients is replacement of fibrinogen to a level of > 0.8 g/L, which is usually adequate to maintain haemostasis. Cryoprecipitate has been used as a source of fibrinogen; each bag of cryoprecipitate contains 100250 mg of fibrinogen, but plasma-derived fibrinogen concentrates are preferable, having had virus inactivation and are licensed for this indication. The usual starting dose for adults is 12 g in-
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travenously. In thrombotic events, patients receive anticoagulation therapy. Recurrent spontaneous first-trimester loss is prevented by regular fibrinogen concentrates to maintain fibrinogen levels greater than 1 g/L starting early in pregnancy. To prevent excessive bleeding during surgical procedures, such as a caesarean section, treatment to raise fibrinogen levels to 1.01.5 g/L during the procedure and for 414 days following surgery should be given. Thromboprophylaxis should be considered, especially in dysfibrinogenaemic patients.
FURTHER READING
Birchall E, Murphy M, Kaplan C, Kroll H; on behalf of the European Fetomaternal Alloimmune Thrombocytopenia Study Group. European collaborative study of the antenatal management of feto-maternal alloimmune thrombocytopenia. Br J Haematol 2003;122:275288. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 2003;120:574596. Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes following maternal exposure to rituximab. Blood 2011;117:14991506. Chalmers E, Williams M, Brennand J, Liesner R, Collins P, Richards M; Paediatric Working Party of United Kingdom Haemophilia Doctors Organization. Guideline on the management of haemophilia in the fetus and neonate. Br J Haematol 2011;154:208215. Chi C, Lee CA, Shittagh N, Khan A, Pollard D, Kadir RA. Pregnancy in carriers of haemophilia. Haemophilia 2008;14:5664. Fakhouri F, Rumeninia L, Provot F, et al. Pregnancy-associated haemolytic uraemic syndrome revisited in the era of complement gene mutation. J Am Soc Nephrol 2010;21:859869. Hunt BJ, Thomas-Dewing RR, Bramham K, Lucas SB. Preventing maternal deaths due to acquired thrombotic thrombocytopenic purpura. J Obstet Gynaecol Res 2013;39:34750. Lee CA, Chi C, Pavord SR, et al. The obstetric and gynaecological management of women with inherited bleeding disorders review with guidelines produced by a taskforce of UK Haemophilia Centre Doctors Organization. Haemophilia 2006;12:301336. Levi M. Disseminated intravascular coagulation (DIC) in pregnancy and the peri-partum period. Thromb Res 2009;123(suppl 2):S63S64. Michel M, Novoa M, Bussel J. Intravenous anti-D as treatment for immune thrombocytopenic purpura (ITP) during pregnancy. Br J Haematol 2003;123:142146. Myers B. Diagnosis and management of maternal thrombocytopenia in pregnancy. Br J Haematol 2012;158:315.
Other Inherited Bleeding Disorders Rare inherited bleeding disorders such as prothrombin deficiency, FV, FII, FX and FXIII deficiencies, and combined FV and FVIII deficiency should be managed jointly with the local haemophilia centre. Acquired Haemophilia Acquired haemophilia is due to the presence of an antibody (inhibitor), usually against FVIII. Typically, this develops 14 months post partum and rarely ante partum. Usually, the antibody disappears spontaneously after a few months. The clinical presentation is with prolonged bleeding, postpartum haemorrhage, menorrhagia, or soft tissue haematomas with a prolonged activated partial thromboplastin time. In contrast with inherited haemophilia, acquired haemophilia does not typically present with haemarthrosis. These patients require management by a haemophilia centre. Thromboprophylaxis in Pregnancy and the Puerperium Even in those with an existing bleeding disorder or bleeding during pregnancy, there is a need for adequate thromboprophylaxis, given the high rate of venous thromboembolism associated with pregnancy and the puerperium.
2012 Elsevier Ltd. Initially published in Obstetrics, Gynaecology and Reproductive Medicine 2012;22(12):339346.
About the Authors

Eleftheria Lefkou is Consultant Haematologist, Blood Transfusion Unit, Hippokrateion University Hospital of Thessaloniki, Greece. Beverley J Hunt is Professor of Thrombosis & Haemostasis, Kings College, and a Consultant at the Department of Haematology, Lupus & Pathology, Guys & St Thomas NHS Foundation Trust, London, UK.
PAEDIATRIC S OBSTETRICS OBSTETRICS
II
Imaging Paediatric Postpartum Pyrexia Brain Tumours

Kevin G Glackin, MB, ChB, BAO, MRCOG, DFSRH; Margaret Ann Harper, OBE, MD, FRCOG, FRCPI, FFSRH Tang Phua Hwee, MBBS, FRCR, MMed Diagnostic Radiology
INTRODUCTION
Postpartum pyrexia is common and is usually due to bacterial infection of the breast, urinary or genital tracts. Although most cases are easily treated with routine management including antibiotics, serious maternal morbidity and occasional mortality can occur. Postpartum or puerperal pyrexia are general terms and exact definitions vary (Box 1). A temperature rise above 38C (100.4F) maintained over 24 hours or recurring during the period from the end of the first to the end of the 10th day after childbirth or abortion is often used (ICD-10).
INCIDENCE
Maternal mortality is the most serious outcome of postpartum pyrexia. Puerperal sepsis, which often occurred in major epidemics, was the leading cause of maternal death in the developed world in the eighteenth, nineteenth and early twentieth centuries. Semmelweiss demonstrated significant improvements in 18461847 by the introduction of careful hand washing between attending each patient; this gradually became widespread practice, but it was only when antibiotics became widely available in the 1940s that the mortality from genital tract sepsis began to decline rapidly. In the triennium 20062008, genital tract sepsis was, for the first time since the UK Confidential Enquiries into Maternal Deaths began in 1952, the commonest cause of direct maternal death in the United Kingdom. This is partly due to decreases in the numbers of deaths from other direct causes, particularly thromboembolism, and partly due to a genuine
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rise in the number of deaths from sepsis, particularly sepsis due to group A streptococcal infection. In 20062008, there were 26 direct maternal deaths from genital tract sepsis; another three women died later but had developed sepsis around the time of delivery. Worldwide, puerperal sepsis remains a major cause of maternal mortality and is estimated to account for approximately 15% of all direct maternal deaths. Postpartum infections are also an important cause of maternal morbidity. The incidence of severe infections and near miss events is much higher than the number of deaths, although accurate figures are hard to find because of the variety of definitions used and the difficulty of obtaining data from the community as many postpartum infections occur after discharge from hospital. The global incidence of puerperal sepsis is estimated to be 4.4% of live births. The Scottish Confidential Audit of Severe Maternal Morbidity showed a rate of septicaemic shock of 0.11 per 1,000 births in the triennium 20062008. The 2011 National Institute for Health and Clinical Excellence (NICE) guideline on caesarean section recommends routine antibiotic prophylaxis to reduce the incidence of infections such as endometritis, urinary tract and wound infections, which occur in about 8% of women who have had a caesarean section. A 2-year study of severe maternal sepsis in the UK was initiated by the UK Obstetric Surveillance System in June 2011.
Box 1. Definitions of postpartum pyrexia and puerperal sepsis.
Although often used to describe any infection of the genital tract after delivery, puerperal infection (or postpartum pyrexia, puerperal pyrexia, or puerperal fever) was considered by the World Health Organization (WHO) Technical Working Group (1992) as a more general term that includes not only infections due to genital tract sepsis, but also all extra-genital infections and incidental infections. The International Classification of Diseases (ICD-10) defines postpartum (puerperal) sepsis as a temperature rise above 38C (100.4F) maintained over 24 hours or recurring during the period from the end of the first to the end of the 10th day after childbirth or abortion. The WHO Technical Working Group (1992) defined puerperal sepsis as infection of the genital tract occurring at any time between the rupture of membranes or labour, and the 42nd day postpartum in which two or more of the following are present: {{ Pelvic pain {{ Fever, ie, oral temperature 38.5C (101.3F) or higher on any occasion {{ Abnormal vaginal discharge, eg, presence of pus {{ Abnormal smell/foul odour or discharge {{ Delay in the rate of reduction of size of the uterus (< 2 cm/day during the first 8 days).
quences of persistent or relapsing maternal infection are serious, so the search for a cause must be pursued vigorously and prompt effective treatment given. Most cases of postpartum pyrexia are related to the recent pregnancy and labour. After delivery, the placental bed, caesarean section and episiotomy wounds, and cervical and vaginal lacerations are all susceptible to bacterial infection. Organisms may be acquired by contamination from an external source or endogenously from the womans own genital tract. Prolonged rupture of membranes, prolonged labour, operative vaginal delivery, caesarean section, pre-existing vaginal infection or history of group B streptococcal (GBS) infection, postpartum haemorrhage, wound haematoma, retained pieces
AETIOLOGY
Postpartum pyrexia may have a wide variety of underlying causes. These may be broadly divided into those directly related to pregnancy, eg, breast or uterine infection (Box 2), and coincidental causes unrelated to pregnancy, eg, malaria (Box 3). The cause of the raised temperature is usually easily discovered but can be elusive. The potential conse-
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Box 2. Postpartum pyrexia: causes related to pregnancy.
HISTORY
A thorough, systematic history is essential to elicit any risk factors for infection and all relevant symptoms, and will usually provide a good idea of the source of infection. The patient may feel generally unwell, shivery, feverish, or complain of rigors, headache, nausea, vomiting, diarrhoea, heavy or offensive lochia, dysuria, abdominal, renal angle or other pain. There may be several symptoms relating to more than one system. Although pregnancy is over, the underlying reason for the raised temperature may originate in events that occurred before or during labour. Therefore, as much information as possible about the recent pregnancy and delivery should be obtained, and the following questions considered: Was there any vaginal or urinary tract infection during pregnancy?
Genital tract causes Endometritis Infection of myometrium or parametrium Pelvic abscess Caesarean wound infection Infection of episiotomy or vaginal or cervical tears Non-genital tract causes Urinary tract cystitis or pyelonephritis Breast infection mastitis or breast abscess Respiratory infection including pneumonia Venous thromboembolism Septic thrombophlebitis Infection of cannula sites including epidural cannulae
Box 3. Postpartum pyrexia: causes unrelated to pregnancy.
Appendicitis Cholecystitis Pancreatitis Respiratory tract infections Cerebral abscess Rheumatic endocarditis Myocarditis Infectious diseases, eg, malaria, tuberculosis, human immunodeficiency virus/AIDS Malignant disease, eg, lymphomas Parasitic infection Drug fever Other
Was a cervical suture inserted during preg nancy? Is there any history of GBS infection? What was the time between rupture of mem branes and delivery? Was the temperature elevated during labour? If caesarean section was performed, was it an elective procedure or after a long labour? or caesarean section wound? Have there been any problems with a perineal Was there excessive bleeding at the time of delivery? Was there any difficulty with delivery of the
of placenta, membranes or intrauterine clot, or retained swabs all increase the risk of postpartum infection. Pregnancy itself affects the immune system, and conditions such as anaemia, impaired glucose tolerance or diabetes mellitus reduce resistance to infection. Obesity, an increasing problem in the developed world, is a risk factor for sepsis, as is multiparity.
placenta or membranes? oured or smell offensive?
Has the lochia been unusually heavy, discol Is there any abdominal pain or tenderness? Is there any pain on micturition? Is the baby breast- or bottle-fed? Is there any history of cracked nipples or mas titis?
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Postpartum pyrexia can be caused by pregnancy-related infections as well as coincidental causes unrelated to pregnancy.
Has the Hasbaby the baby any evidence any evidence of infection? of infection? Are any other family members affected by sim ilar symptoms? In hospital, the patients obstetric and midwifery notes should be reviewed. In the community, the hospital discharge note should include all relevant clinical information, but this does not always happen. If necessary, the hospital may be contacted for further information. Good communication between hospital and community carers is emphasized in the maternal mortality report Saving Mothers Lives 20032005.
was absent. Labour was induced and she delivered a stillborn baby. Two days following delivery, she developed a pyrexia. Blood cultures were taken, and she was commenced on intravenous antibiotics. Within 24 hours, she deteriorated, developing shortness of breath, tachycardia and continued pyrexia. She was investigated for suspected pulmonary embolus, which was excluded, but deteriorated further and was admitted to the intensive care unit. She was treated for a lower respiratory tract infection and adult respiratory distress syndrome. Blood cultures were positive for coliforms. This history illustrates that a woman can deteriorate rapidly. This woman had a risk factor for sepsis in the history of PPROM. The time scale from developing first signs to progressing to a lifethreatening state can be very short. Prompt assessment and treatment are essential. It is important to check temperature, examine the lochia, and check
Case 1 A multiparous woman was admitted with pre-term pre-labour rupture of membranes (PPROM) at 32 weeks gestation. She was commenced on oral erythromycin and given intramuscular corticosteroids. Two days after admission, the fetal heart
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for other sources of infection including the breasts. It is important to examine the legs and chest for signs of thromboembolism which may also manifest in pyrexia. It is important to consider how long the membranes ruptured before delivery. PPROM is associated with infection and should raise the index of suspicion. In postpartum pyrexia, attention should be paid to all symptoms, not only those related to the genital tract. Pain in the upper abdomen, head, chest or legs, presence of a rash, alteration in mental state or level of consciousness, presence of cough or haemoptysis, or any other symptom, should prompt further enquiry, consideration of other non-pregnancy-related diagnoses and appropriate investigation.
was mistakenly and tragically assumed to be having panic attacks because she had a known history of these. She was admitted to a psychiatric hospital and, although rapidly transferred to the local general hospital, died soon afterwards. Autopsy revealed an infected necrotic uterus.
In postpartum pyrexia, attention should be paid to all symptoms, not only those related to the genital tract
Is It Necessary to Monitor Maternal Temperature After Delivery? In hospital, monitoring of maternal temperature measurement during labour and after vaginal delivery or caesarean section is routine, but is not usually done after the woman returns home. The 2006 NICE guideline on postnatal care advises that routine assessment of temperature is unnecessary in the absence of any signs or symptoms of infection, but should be taken and documented if infection is suspected. The guideline also recommends that if the temperature is above 38.0C, measurement should be repeated within 46 hours, and if still elevated or there are other observable symptoms and measurable signs of sepsis, further evaluation and emergency action should be taken.
EXAMINATION OF PATIENTS WITH POSTPARTUM PYREXIA

The abdomen should be examined for tenderness and masses and the uterus palpated to assess its
It is important to keep an open mind and not assume causes without reviewing all the evidence, taking all the symptoms and clinical findings into consideration, and being prepared to change the provisional diagnosis if new factors come to light. Severe sepsis can cause systemic symptoms or confusional states that may mislead the clinician, as illustrated by one case in the triennial report Why Mothers Die 20002002 of a woman with a persistent tachycardia (130170 beats per minute) and increasingly bizarre behaviour after delivery, who
size and tenderness. If present, the abdominal wound should be inspected for signs of infection, haematoma or dehiscence, and the bowel sounds auscultated. The lochia and perineal wound, if present, should be inspected for evidence of infection. The breasts should be examined for any redness, tenderness, localized masses, or cracked nipples. The heart sounds should be auscultated and lung fields checked for any signs of infection. The legs should be inspected for signs of deep venous thrombosis such as tenderness along the course of
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the deep veins or unilateral oedema of the lower leg. If there are any other signs or symptoms such as sore throat or lymphadenopathy, appropriate examination should be performed.
Box 4. Initial investigations for postpartum pyrexia.
INVESTIGATIONS
The initial blood and microbiological investigations that should be performed in a woman presenting with postpartum pyrexia are listed in Box 4. Even if microbiological tests are negative, swabs, blood and urine cultures should be repeated at intervals if the patient remains unwell. Ultrasound of abdomen and pelvis is indicated to assess uterine size and involution, and look for any retained products of conception. Most cases of postpartum pyrexia are pregnancy-related, but if investigations have ruled this out and pyrexia persists despite appropriate treatment, then other causes need to be considered. Advice about possible causes and appropriate further investigations from physicians, microbiologists, specialists in infectious diseases or other specialists may be helpful. Additional investigations may include blood films, antinuclear antibodies and rheumatoid factor, tests for infections such as hepatitis, human immunodeficiency virus, tuberculosis, cytomegalovirus, glandular fever and Q fever, chest and abdominal X-rays, electrocardiogram, Doppler examination of leg and pelvic veins, and ventilation-perfusion scan to look for evidence of venous thromboembolism, computed tomography of the abdomen which may detect intra-abdominal or renal abscesses, or transoesophageal echocardiography to detect bacterial vegetations on the heart valves. Rheumatic heart disease used to be the commonest underlying cause of indirect maternal death but is now rare in the UK. Nevertheless, rheumatic fever is still common in other parts of the world,
Blood tests Full blood count (white cell count) C-reactive protein Blood cultures (aerobic and anaerobic) Blood gases, lactate and coagulation screen if patient is clinically unwell Urea and electrolytes Liver function tests Serum amylase D-dimer Microbiology High and low vaginal swabs Urine microscopy and culture Throat, wound, rectal swab or other swabs may be indicated Sputum culture if productive cough Breast milk if mastitis suspected
and women recently arrived from developing countries may have this condition. Two maternal deaths occurred from infectious endocarditis in the triennium 20032005.
Case 2 A young woman in her second pregnancy had a spontaneous normal delivery in the midwifery-led unit and went home after 8 hours. The community midwife visited her on day 3, when she was found to have pyrexia of 39C associated with rigors but no other symptoms. On examination of the breasts by the midwife, one breast was tender, red and hot. The woman had thought this was to be expected as she was breastfeeding. A diagnosis of mastitis was made, and the woman was commenced on oral antibiotics. A full physical examination is indicated in the assessment of a woman with postpartum pyrexia. Breast infection is a pregnancy-related cause of pyrexia but often not immediately considered as it is outside the genital tract. In addition, women may not volunteer breast symptoms as they may consider pain or enJPOG JAN/FEB 2013 33
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gorgement in the breast to be normal. Breast infections can be difficult to treat, and it is important to prescribe adequate dosage of an antibiotic, such as flucloxacillin 500 mg orally four times a day, and to continue treatment for 1014 days to ensure that infection has been eradicated.
changes in the patients condition and help the earlier recognition of women who have or are developing a critical illness. This is one of the top ten key recommendations in the triennial reports of the Confidential Enquiries into Maternal Deaths in the United Kingdom for 20032005 and 2006 2008. If a patient is more seriously ill, or shocked, tachycardic, hypotensive (systolic blood pressure < 90 mm Hg), breathless or otherwise distressed, thinking of the sepsis six is an aid to prompt management. This refers to six simple steps that can be performed easily by non-specialist staff within 1 hour of recognizing severe sepsis: Give 100% oxygen Take blood cultures Give intravenous antibiotics Start intravenous fluid resuscitation Check haemoglobin and lactate Insert urinary catheter and measure hourly urine output. Initial investigations including microbiology
MANAGEMENT OF POSTPARTUM PYREXIA

Postpartum pyrexia requires prompt intervention. In the community, urgent assessment is appropriate, with referral for hospital assessment and admission if the patient is generally distressed or unwell, or has pyrexia of 38C or more, or is breathless, or has sustained tachycardia, or has severe diarrhoea or vomiting, or has chest, abdominal, uterine, renal angle or other pain. In hospital, immediate observations of temperature, pulse, blood pressure, respiratory rate,
Sepsis can have a very rapid and fulminating course, and adequate early intravenous antibiotic treatment may be lifesaving
should be carried out as soon as possible. Treatment with a combination of high-dose, broad-spectrum, intravenous antibiotics such as co-amoxiclav and metronidazole should be started immediately, within an hour of admission, without waiting for microbiology results. This is because sepsis can have a very rapid and fulminating course, and adequate early intravenous antibiotic treatment may be lifesaving. The onset of septicaemia in a previously healthy young woman is often insidious, but as the disease advances her clinical condition may deteriorate very rapidly and she may collapse
quality and amount of lochia, pain score, and level of consciousness should be made, and then repeated at regular intervals appropriate to the patients condition. It is sometimes difficult to know whether a patient is seriously ill. Routine use of a comprehensive obstetric early warning scoring chart will show
suddenly. If there is no response to the initial antibiotic regimen within 2448 hours or the patients condition worsens, the antibiotics should be changed and gentamicin or similar antibiotic added. It is very helpful to seek advice from a consultant microbiologist.
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The reports of the UK Confidential Enquiries into Maternal Deaths emphasize the importance of seeking consultant advice as soon as possible after the patient is recognized to be seriously ill. It is important to involve consultant anaesthetists, the critical care team, consultant microbiologist, and members of other disciplines such as radiology, surgery or haematology as appropriate, depending on the situation. The need for high dependency or critical care should be anticipated and, if possible, planned in advance as a bed may not be immediately available. Even if there is no critical care bed, appropriate resuscitation and intensive care can be commenced in other settings. The cause of pyrexia should be elucidated and the appropriate treatment for the underlying condition commenced as soon as possible. This may
Practice points
A complete history, full physical examination, blood and urine cultures, and swabs from the vagina, any wound, and throat if symptomatic are essential in cases of postpartum pyrexia. Regular frequent observations should be made, and the use of an early warning score chart will help to detect early changes in the patients condition. Patients with systemic infection can deteriorate very rapidly, so it is essential to commence high-dose, broad-spectrum, intravenous antibiotics immediately without waiting for results of microbiological investigations. If the cause of pyrexia is not quickly obvious, a variety of further investigations will be needed and advice should be sought from senior colleagues in other disciplines.
include laparotomy and surgical drainage of ab- advent of antibiotics and antisepsis. This recent scesses. re-emergence of cases has prompted the need for antenatal education regarding personal hygiene and specific advice to women to avoid inadvertent contamination of the perineum by washing hands before using the toilet, changing sanitary pads/tampons, etc. Contamination is more likely when the woman or close family, particularly children, have sore throat and/or respiratory symptoms.
Case 3 A 26-year-old woman at 28 weeks gestation in her first pregnancy was admitted following diagnosis of intrauterine death. Labour was induced, and she delivered a stillborn baby. Within 24 hours of delivery, she developed pyrexia and shortness of breath. Blood cultures were obtained, and she was commenced on broad-spectrum intravenous antibiotics. She was admitted to the high dependency unit following further deterioration including respiratory distress. Blood cultures were positive for group A Streptococcus. The triennial report of The Confidential Enquiry into Maternal Death in the UK for 20062008 reports 13 deaths from beta-haemolytic Streptococcus Lancefield group A (Streptococcus pyogenes ). This compares with eight deaths for 20032005 and three deaths in 20002002. This organism has historically been associated with puerperal sepsis, but maternal mortality was reduced following the
PREVENTION OF POSTPARTUM GENITAL TRACT INFECTION

Strict attention to hygiene, frequent hand washing, and aseptic precautions for all procedures performed during labour and delivery are essential. Frequent vaginal examinations should be avoided, as they increase the risk of introducing infection to the genital tract. When membranes rupture prior to the onset of labour, manual vaginal examination should be avoided altogether although a sterile speculum may be used to examine the cervix, exclude cord prolapse, and take a swab for bacteriological exJPOG JAN/FEB 2013 35
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amination. The 2003 Royal College of Obstetricians and Gynaecologists (RCOG) Green-top Guideline about group B streptococcal (GBS) disease recommends that when there is a history of GBS infection, intravenous antibiotic prophylaxis should be given with penicillin 3 g as soon as possible after onset of labour then 1.5 g 4-hourly until delivery, or clindamycin 900 mg 8-hourly for those allergic to penicillin; although if chorioamnionitis is suspected, broad-spectrum antibiotic therapy including an agent active against GBS should replace GBSspecific antibiotic prophylaxis. The placenta and membranes should always be examined carefully after delivery to ensure that they are complete. All swabs, needles and instruments used should be checked and accounted for at the end of any procedure, including repair of episiotomy and all other vaginal procedures. The 2011 NICE Caesarean Section Guideline recommends that a single dose of a prophylactic broadspectrum antibiotic, such as ampicillin or a firstgeneration cephalosporin, be offered to all women having a caesarean section. The 2007 RCOG Greentop Guideline about the management of a third- or fourth-degree perineal tear recommends the use of broad-spectrum antibiotics, including metronidazole, to reduce the incidence of postoperative infections and wound dehiscence. The 2011 RCOG Green-top Guideline about operative vaginal delivery notes that there is insufficient evidence to make recommendations regarding prophylactic antibiotics; however, good standards of hygiene and aseptic technique are recommended. Although there are no randomized controlled trials of the use of prophylactic antibiotics for manual removal of retained placenta after vaginal birth, a 2009 Cochrane Database Review suggests following World Health Organization advice of a single dose of metronidazole 500 mg intravenously plus either ampicillin 2 g or cefazolin 1 g intravenously.
CONCLUSION
Postpartum pyrexia is a significant finding, which requires a full history and examination, thorough investigation, close observation, and prompt treatment. Most cases are due to genital tract sepsis, but some are due to a wide variety of other causes. A range of further investigations may be required, and advice from senior colleagues in other specialities, particularly microbiology, haematology, anaesthesia and critical care, should be sought at an early stage.
FURTHER READING
Bacterial sepsis following pregnancy. Green-top Guideline No. 64b. Royal College of Obstetricians and Gynaecologists, April 2012. Centre for Maternal and Child Enquiries (CMACE). Saving mothers lives: reviewing maternal deaths to make motherhood safer: 200608. The Eighth Report on Confidential Enquiries into Maternal Deaths in the United Kingdom. BJOG 2011;118(suppl 1):1203. Maharaj D. Puerperal pyrexia: a review. Part I. Obstet Gynecol Surv 2007;62:393399. Maharaj D. Puerperal pyrexia: a review. Part II. Obstet Gynecol Surv 2007;62:400406. Palaniappan N, Menezes M, Willson P. Group A streptococcal puerperal sepsis: management and prevention. The Obstetrician & Gynaecologist 2012;14:916. Sinha P, Otify M. Genital tract sepsis: early diagnosis, management and prevention. The Obstetrician & Gynaecologist 2012;14:106114. UKOSS UK Obstetric Surveillance System. https://www.npeu. ox.ac.uk/ukoss.
2012 Elsevier Ltd. Initially published in Obstetrics, Gynaecology and Reproductive Medicine 2012;22(11):327332.
About the Authors

Kevin G Glackin is a Specialty Trainee (ST7) in Obstetrics and Gynaecology at Altnagelvin Hospital, Londonderry, UK. Margaret Ann Harper is a Consultant in Obstetrics and Gynaecology at Royal-Jubilee Maternity Service, Belfast, UK.
TH Cheung, MBBS(HK), MRCOG(UK), MHKCOG, FHKAM(O&G)
INTRODUCTION
Endometrial cancer (EC) is the fourth most common malignancy in women worldwide. About 290,000 cases are diagnosed annually, leading to 74,000 deaths.1 The standard treatment has been total abdominal hysterectomy and bilateral salpingo-oophorectomy (THBSO), and pelvic and aortic lymphadenectomy, followed by adjuvant pelvic irradiation for those with high clinical-pathological risk factors. Recent clinical studies have raised queries and challenges to the conventional treatment approach. This article gives an overview of this malignant disease, discusses the controversies, summarizes the current position, and highlights the possible treatment strategies in the future.
Table 1. Comparison of FIGO 1988 with FIGO 2009 staging systems for endometrial carcinoma FIGO 1988 Limited endometrium < myoinvasion > myoinvasion Cervical glands involvement Cervical stromal involvement Tumour invades the serosa and/or adnexae Positive peritoneal washing Vaginal and/or parametrial involvement Pelvic node metastasis Aortic node metastasis Bladder and/or bowel mucosa involvement Distant metastasis Stage IA Stage IB Stage IC Stage IIA Stage IIB Stage IIIA Stage IIIA Stage IIIB Stage IIIC Stage IIIC Stage IVA Stage IVB FIGO 2009 Stage IA Stage IA Stage IB Not relevant Stage II Stage IIIA Not relevant Stage IIIB Stage IIIC1 Stage IIIC2 Stage IVA Stage IVB
usually diagnosed at early stage and have
RISK FACTORS
Chronic anovulation in premenopausal women and peripheral conversion of androstenedione secreted from the adrenal gland in the adipose tissue of overweight postmenopausal women are the common sources of unopposed oestrogen. Breast cancer survivors taking tamoxifen also has a sevenfold higher relative risk of developing EC.4 A recent cohort study suggests that increased EC risk is associated with the use of combined oestrogen and proJPOG JAN/FEB 2013 37
PATHOLOGY
Two distinct types of EC have been defined based on histology and molecular characteristics of the tumour (Table 1). Type I tumour or endometrioid carcinoma accounts for 8090% of all EC. 2 It is related to unopposed oestrogen stimulation and is preceded by atypical hyperplasia. The typical molecular alterations include PTEN gene silencing and defects in DNA mismatch repair genes. Patients with type I EC are
3
a 5-year survival rate of 74%. Type II tumour includes clear cell, papillary serous adenocarcinoma and carcinosarcoma. It is not oestrogen-related and develops from atrophic endometrium. In contrast to type I tumours, p53 gene mutation, p16 gene inactivation and Her2/neu overexpression are often found. Patients are more often diagnosed at late stage because the tumour spreads early, and the overall 5-year survival rate is between 27% and 42%.
3
Figure 1. Endometrial carcinoma with full thickness infiltration. a) Magnetic resonance imaging. b) Intraoperative finding: tumour invades through the serosa of the anterior uterine wall. c) Uterine specimen cut open.
gestogen replacement for more than 10 years among women with body mass index below 25 kg/m2.5 Lynch syndrome, or hereditary nonpolyposis colon cancer (HPNCC), is due to germline mutation of one of the mismatch repair genes, and it accounts for 23% of all EC and 9% of EC diagnosed before the age of 50. The cumulative risk of a HPNCC patient developing EC reaches 60% by the age of 70.
6
Dilatation and curettage (D&C) under general anaesthesia used to be performed for patients with abnormal uterine bleeding, but outpatient procedures including
9
raphy, as the negative predictive value is 99% and 100%, respectively. 15,16 Whether transvaginal ultrasonography, endometrial biopsy, and hysteroscopy, alone or in combination, is used to investigate abnormal uterine bleeding depends on the availability of expertise. Since none of the tests is 100% sensitive, further investigation is indicated if the symptom persists.
Vabra aspirator and Pipelle are preferred nowadays. Although the Vabra aspirator can sample a larger endometrial surface,10 a meta-analysis showed that Pipelle outperforms the Vabra aspirator and offers a sensitivity of 99.6% and 91% for diagnosing EC in postmenopausal and premenopausal women, respectively.
11
A positive association between EC and metabolic syndrome factors including obesity, hypertension, hyperglycaemia and hyperlipidaemia, alone or in combination, has also been suggested by a prospective study.
7
PREOPERATIVE INVESTIGATION
Many EC patients are old, obese and have significant medical problems including diabetes mellitus and hypertension. Thorough health assessment and optimization are essential before treatment to minimize complications. Contrast-enhanced magnetic resonance imaging (MRI) is preferred to computed tomography (CT) in assessing the uterine and tumour size, myoinvasion, cervical invasion, and nodal metastasis17 (Figure 1). The overall staging accuracy rate is 8593%. Positron emission tomography/CT is the most sensitive method in detecting nodal metastasis but does not
Hysteroscopy offers visual-guided biopsy of the lesion inside the uterus. A meta-analysis showed that hysteroscopy had a high diagnostic accuracy rate and low serious complication rate, and the failure rate of the procedure was 3.6%.
12
CLINICAL PRESENTATION AND DIAGNOSIS

EC patients usually present with abnormal uterine bleeding. Occasionally, EC may be diagnosed in asymptomatic women who have atypical glandular cells on Papanicolaou smear. The median age of EC patients is 61, and 20% of EC patients are premenopausal.
8
The increased incidence of positive peritoneal cytology in patients with EC after hysteroscopy raises concerns even though there is no evidence that the procedure promotes dissemination of cancer and worsens the prognosis.13,14 Further investigations may not be necessary for postmenopausal women with endometrial thickness < 5 mm or < 4 mm measured by transvaginal ultrasonog-
provide accurate information on the primary tumour and is therefore not routinely recommended.18 CA-125 may be checked before surgery, and the level is raised in a third of EC patients.19 Patients with abnormal CA125 are more likely to have higher tumour grade and deep myoinvasion, nodal metastasis, and poor survival.20 The International Federation of Gynecology and Obstetrics (FIGO) adopted a surgical staging system for EC in 1988 to replace the previously used clinical staging system that failed to categorize patients into different prognostic groups accurately. The surgical staging system has been revised in 2009, and the changes are shown in Table 1.
21
Table 2. Endometrial carcinoma classified into three different risk groups Grade I Stage IA Low Grade II Low Grade III Intermediate (without LVSI) High High
Stage IB Intermediate Intermediate Stage II and above High High

LVSI = lymphvascular space invasion.
offered to surgically fit EC patients with cervical involvement, but clear survival benefit from aggressive surgery is not available.
21
appears to more appropriate. However, the current technology is imprecise in determining these two tumour characteristics before or during surgery. Among 181 clinical stage I EC patients that had grade 1 tumour, 18% of the patients needed an upstage and 19% had tumours upgraded in the final pathology.23 High-quality and efficient intraoperative frozen pathological assessment may provide the answer, but such a service is not readily available.
Therapeutic Lymphadenectomy
Preoperative irradiation has
not been shown to offer any benefit and has largely been abandoned.
Staging Lymphadenectomy
Based on the FIGO staging together with histopathological risk factors such as tumour grade, histological type and lymphvascular space invasion, EC patients can be roughly assigned to three risk groups to guide the treatment (Table 2).
22
Since only 10% of stage I EC patients have pelvic nodal metastasis and about 50% of the nodal metastasis are noticeable intraoperatively,
22
routine pelvic and paraRetrospective studies suggest that multiple-site lymphadenectomy, removal of a larger number of lymph nodes, and debulking of enlarged metastatic nodes offer survival benefits.2426 However, the therapeutic benefit of pelvic lymphadenectomy was not supported by two recently published randomized clinical trials (RCTs). An Italian study randomized FIGO clinical stage I EC patients to systematic pelvic lymphadenectomy or no lymphadenectomy after hysterectomy. Significantly more patients in the pelvic lymphadenectomy group compared with those in the nolymphadenectomy group were diagnosed to have nodal metastasis (13.3% vs 3.2%)
aortic lymphadenectomy to all patients including those with no enlarged nodes may represent an overtreatment because the chance of finding nodal metastasis is low. Performing pelvic lymphadenectomy only is insufficient to ascertain the nodal status because metastasis to the aortic node can occur without involving the pelvic node. Omitting lymphadenectomy for patients with FIGO stage IA disease, grade 1 to 2 tumour is justifiable because the risk of nodal metastasis is well below 10% and their 5-year survival rate is above 95% after THBSO. Restricting pelvic and para-aortic lymphadenectomy up to the level of renal vein in EC patients with high tumour grade and deep myoinvasion
MANAGEMENT OF ENDOMETRIAL CARCINOMA

Surgical Treatment
Hysterectomy and Bilateral Salpingooophorectomy
Surgery is the mainstay of treatment, and THBSO is recommended not only to patients with early-stage disease but also to the 1025% patients diagnosed with stage III or IV disease. Bilateral salpingooophorectomy is recommended because of the potential risk of tumour metastasis to the ovary. Radical hysterectomy may be
and developed postoperative complications. However, the 5-year disease-free survival and overall survival (OS) were similar between the two groups.26 A Study in the Treatment of Endometrial Cancer (ASTEC) trial randomized patients to THBSO with or without lymphadenectomy. Patients diagnosed to have intermediate-/high-risk early-stage disease were subjected to a second randomization to pelvic radiotherapy or no radiotherapy postoperatively. The progression-free survival (PFS) and OS were not different between the two groups.
Surgical Approaches
27
Robot-assisted technique is an advanced mode of minimally invasive surgery, and the major advantages of robotassisted surgery are a steep learning curve and no association between an increase in body mass index and a higher conversion rate.
30,31
attributable to vault recurrence. Because most patients with vault recurrence could be salvaged and about 50% of deaths were not related to the EC or treatment, survival benefit of RT again was not demonstrated. A Study in the Treatment of Endometrial Cancer (ASTEC) and EN.5 trials were two distinct studies, and their data were pooled in a planned analysis. Primary surgery did not always include lymphadenectomy, and the patients were randomized to postoperative external beam RT or observation. The 5-year survival rates were 84% in both groups.34 The GOG 99, PORTEC and ASTEC+EN.5 studies have shown no evidence of survival benefit by giving external RT, but the treatment-related morbidity would be significantly higher. 3234 Since vaginal vault recurrence is the most common site of recurrence, the PORTEC-2 study randomized high-intermediate-risk patients to external beam RT or vaginal brachytherapy (VBT). The estimated rates of vaginal recurrence were 1.8% for VBT and 1.6% for external beam RT. There were no differences in the overall and disease-free survival between the two groups, but the acute gastrointestinal toxicity was significantly lower in the VBT group (13% vs 54%). VBT is therefore recommended for high-intermediate-risk EC patients and routine pelvic RT is not.35 Chemotherapy
Chemotherapeutic Regime
Pelvic Irradiation Adjuvant external beam pelvic radiation therapy (RT) is often given to patients with risk factor for nodal metastasis or patients with documented nodal metastasis. However, there has never been any evidence to support that pelvic RT improves the survival. Recently published studies have further questioned the role of adjuvant pelvic RT in intermediate-risk EC patients. The Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) study randomized intermediate-risk EC patients to adjuvant pelvic RT and no further treatment after THBSO. After a median
32
The Gynecologic Oncology Group (GOG) LAP2 study compared laparoscopic with open surgery for treating patients with stage I to IIA EC. The surgical treatment consisted of extrafascial hysterectomy, bilateral salpingo-oophorectomy, and pelvic and aortic node dissection. Laparoscopic approach was associated with longer operative time, less postoperative morbidities, and shorter hospital stay. There was no difference in the intraoperative complication rates and the numbers of nodes removed. Nodal metastasis was diagnosed in 9% of patients in both groups. However, one in four patients randomized to the laparoscopic approach ended up requiring conversion to open surgery, and the risk increased with the body mass index and age. It appears that laparoscopic surgery was applicable to EC patients when trained surgeons were available. A meta-analysis
28
follow-up of 52 months, the loco-regional recurrence rates were 4% and 14% in the RT and control groups, respectively, whilst the rates of distant metastasis were not different. Because of the higher rate of successful salvage treatment in the control group (79% vs 21%), the actuarial 5-year OS rates (81% vs 85%) and the ECrelated death rates (9% vs 6%) were not significantly different between the two groups. The GOG 99 study randomized intermediate-risk node-negative EC patients to external beam RT or observation. The
33
showed no difference in the OS, diseasefree survival and cancer-related death between the laparoscopic and open surgery.
29
24-month cumulative recurrence rate was 3% in the RT group and 12% in the control group, and the difference was mostly
Recurrences that commonly occur outside the pelvis or the pelvic irradiation field suggest that systemic therapy may be nec-
essary. Phase II studies showed that taxanes, anthracyclines, ifosfamide and platinum drugs are the most effective agents for EC, and a response rates of 20% can be expected.
3638
III) to pelvic RT or five cycles of cisplatin and doxorubicin, and showed no survival difference between the two treatment arms.42 A Japanese Gynecologic Oncology Group study randomized patients with no residual disease after hysterectomy and pelvic and para-aortic node dissection to chemotherapy or pelvic RT, and again showed no difference in the PFS and OS between the two treatment arms. However, in the subgroup analysis for the high-intermediate risk subgroup defined as stage IC grade 3 and stage II and IIIA disease with deep myoinvasion, PFS and OS were better after chemotherapy.43 The GOG 122 study compared postoperative adjuvant chemotherapy consisting of eight cycles of doxorubicin and cisplatin with whole abdominal irradiation in stage III and IV EC patients with residual disease < 2 cm, and showed that the PFS and OS were better after chemotherapy than whole abdominal irradiation.
44
ganisation for Research and Treatment of Cancer (NSGO/EORTC-55991) with Italian GOG at the Mario Negri Institute (MaNGO ILIADE-III) showed that EC patients with no residual disease after surgery had improved PFS and cancer-specific survival if chemotherapy was given after the completion of pelvic RT compared with those with RT alone; however, the differences in OS were not statistically significant.45 Meta-analysis of nine RCTs on the role of chemotherapy after surgery for EC showed that chemotherapy reduces the risk of recurrence, and improves PFS and OS. 46 It has been estimated that 1 in every 25 patients treated with high-dose platinum-based chemotherapy was cured. Although chemotherapy appears to be effective when used alone or sequentially after RT, further studies are needed to define which patient groups should receive chemotherapy and which chemotherapy regime should be used. Since EC patients might be old and have significant co-morbidities, the clinical benefits of chemotherapy have to be weighed against the toxicity of chemotherapy. Endocrine Therapy EC is considered as an oestrogen-dependent tumour, and progesterone has been used in EC patients after surgery. No particular progestational agent has been shown to be superior to the rest, and the duration of usage varies from months to an indefinite period of time. However, there is no evidence that progestogen treatment after surgery prolongs recurrence-free survival or OS.47 A Cochrane review of progestogen therapy in patients with advanced or reJPOG JAN/FEB 2013 41
One RCT showed higher response rate and longer PFS with combined doxorubicin and cisplatin than with doxorubicin alone. The GOG 177 study further
39
showed that the paclitaxel, doxorubicin and cisplatin (TAP) combination had higher response rate (57% vs 34%) and prolonged PFS (median, 8.3 vs 5.3 months) and OS (median, 15.3 vs 12.3 months) compared with doxorubicincisplatin.
40
TAP has
therefore become the standard treatment in patients with advanced stage or recurrent disease. However, the toxicity of this three-drug combination is significant. Carboplatin combined with paclitaxel (CP) is the standard outpatient regime for ovarian cancer patients and achieves a 4063% response rate when used in chemotherapy-naive EC patients.
41
The
GOG 209 study is a RCT comparing the performance of CP with TAP for stage III and IV or recurrent EC, and the final analysis is pending. Although CP has not been proven to be superior to TAP, it has already been widely used in EC patients because of the high response rate, ease of administration, and manageable toxicity. A number of clinical trials have commenced to determine the role of this combination.
Radiotherapy Versus Chemotherapy
It therefore appears that patients with high-risk features are more likely to benefit from chemotherapy whilst adequately surgically staged low-risk patients with low metastatic risk do not.
Radiotherapy Followed By Chemotherapy
Since chemotherapy appears more effective in reducing distant metastasis whilst radiotherapy is more effective in reducing pelvic recurrence, a sequential use of chemotherapy after RT appears advantageous.
42
An Italian multicentre study randomized patients with high-risk EC (FIGO 1988 stage IC grade 3, stage IIA to IIB grade 3 with deep myoinvasion or greater, or stage
The joint study by Nordic Society of Gynaecological Oncology/European Or-
Key points
(26%).53 Preoperative MRI is performed to assess myoinvasion although the negative predictive value of MRI in predicting absence of myoinvasion is only 4249%.17 Daily 100400 mg megestrol acetate or 200600 mg medroxyprogesterone acetate are most commonly used. Higher response rate was not observed in patients with advanced or recurrent EC treated with 1,000 mg medroxyprogesterone acetate compared with those receiving 200 mg per day.54 A 75% response rate can be expected, and treatment failure should be declared if no response is recorded after a 3-month treatment.55 The treatment duration often extends beyond 6 months if a response is observed. D&C at 3-monthly interval is mandatory after fertility-sparing treatment because 30% of patients would recur even after complete response. About 3050% of responders achieve pregnancy, with or without assistance from reproductive technology. 56 Hysterectomy is advisable after completing the family.
Endometrial carcinoma (EC) is a heterogeneous disease with different histological types characterized by different aberrant molecular changes. EC or type I EC is the commonest histological type that results from unopposed oestrogen stimulation. The cornerstone of treatment of curative intent is surgery for EC. Conventional and minimally invasive surgeries are equally applicable to patients with EC. Lymphadenectomy provides important information for the staging but its therapeutic benefit has not been proven. Pelvic irradiation improves pelvic disease control with no survival benefit. Chemotherapy is the mainstay of treatment for metastatic and advanced EC. Combination chemotherapy is better than single-agent treatment. The carboplatin and paclitaxel combination is commonly used because of high response rate, ease of administration, and manageable toxicity. Hormonal therapy is used for palliation only. Progestogen treatment has more tolerable side effects compared with chemotherapy and is effective mostly for grade 1 EC. Fertility-sparing treatment can only be considered in selected cases after detail counselling. The most frequently altered molecular pathway that leads to uncontrolled cell proliferation and tumour survival is PI3K/PTEN/AKT/mTOR. Vaginal examination is important during follow-up visits because recurrence at the vaginal vault is most common and salvageable.
current EC showed no evidence of survival improvement.48 When progestogen is used for palliation in EC patients with advanced disease or recurrence, a 1156% response rate and PFS time of 2.5 to 14 months might be achieved. Tamoxifen and aro49
sparing treatment using high-dose progestogen is not the standard treatment, and 10% of EC patients below the age of 45 have synchronous ovarian cancer and fertility-sparing treatment is not applicable.
52
Targeted Therapy The PI3K/PTEN/AKT/mTOR pathway is the most commonly activated pathway in type I EC. Temsirolimus is a mTOR inhibitor and can achieve a 414% partial response rate in heavily pretreated and chemotherapynaive EC patients.57 Bevacizumab demonstrated a 15.1% response rate and a median PFS of 4.2 months in patients with persistent or recurrent EC in a phase II study.58 It is likely that targeted treatment should be individualized according to the aberrant genetic changes, and efforts to identify markers that predict response to
matase inhibitors have been used in EC, but the response rates were modest. Fertility-sparing Therapy About 35% of EC patients are below the age of 40, and some of them may have strong desire to preserve fertility.
50,51
Fertility-sparing treatment should only be considered for patients with grade 1 tumour limited to the endometrium, and D&C is needed to assess tumour grade because significantly fewer patients with grade 1 EC diagnosed after D&C (10%) were upgraded to higher tumour grade compared with office endometrial biopsy
It
cannot be overemphasized that fertilityJPOG JAN/FEB 2013 42
targeted therapy are important to maximize the benefits of targeted therapy.
questioned. 60 CA-125 may be used if the marker is raised before treatment. Imaging studies at interval for asymptomatic patients is not routinely recommended.
often used in radiotherapy-naive patients with or without prior surgical debulking. Relapse inside the prior irradiated field is uncommon and is more difficult to treat. Ultra-radical surgery involving multi-visceral resection might be needed although most might not be suitable for this high-risk aggressive approach. Among 44 patients with exenteration, 20% of patients achieved long-term survival of > 5 years.62 Systemic treatment is indicated for patients with multiple-site disease. Hormonal therapy might be used for asymptomatic patients with receptor-positive grade 1 disease, and chemotherapy is used for symptomatic or receptor-negative patients. Currently, there is no Food and Drug Administrationapproved agent for second-line salvage therapy.
POSTOPERATIVE SURVEILLANCE
MANAGEMENT OF About 15% of EC recur, and the common- RECURRENCES

est site of recurrence is at the vaginal vault.
58
Most of the recurrences develop
A meta-analysis has shown that complete surgical cytoreduction in patients with advanced-stage or recurrent EC was associated with improved survival. 59 Treatment of patients with recurrences has to be individualized according to the tumour size, tumour grade, site of recurrence, and prior or no prior irradiation. For patients with vaginal vault recurrence and no prior RT, external beam pelvic RT can effectively treat tumour < 2 cm. For tumour > 2 cm, surgical cytoreduction is advisable before radiotherapy to increase the chance of cure.61 In the PORTEC study, the 3-year survival rate after vaginal relapse was 73%.
32
within the first 2 years and 75% within 3 years after treatment. The National Comprehensive Cancer Network guidelines recommend visits every 3 to 6 months for 2 years then 6 months or annually. More intense follow-up may
59
be indicated if the patient has high risk factor for recurrence or develops morbidities related to the treatment. Patients who develop symptoms, particularly vaginal bleeding or brownish discharge, should be advised to return for early examination to ensure early diagnosis. In the follow-up visits, physical examination of the genital tract is a must. The cost-effectiveness of routine vaginal cytology in asymptomatic women has been
About the Author

Dr Cheung is Consultant and Chief of Service in the Department of Obstetrics and Gynaecology at The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong.
For nodal recurrences that occur at the pelvic sidewall or aortic areas, RT is
REFERENCES
1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:28932917. 2. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 1983;15:1017. 3. Gadducci A, Greco C. The evolving role of adjuvant therapy in endometrial cancer. Crit Rev Oncol Hematol 2011;78:7991. 4. Bergman L, Beelen ML, Gallee MP, Hollema H, Benraadt J, van Leeuwen FE; Comprehensive Cancer Centres ALERT Group. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000;356:881887. 5. Razavi P, Pike MC, Horn-Ross PL, Templeman C, Bernstein L, Ursin G. Long-term postmenopausal hormone therapy and endometrial cancer. Cancer Epidemiol Biomarkers Prev 2010;19;475483. 6. Backes FJ, Cohn DE. Lynch syndrome. Clin Obstet Gynecol 2011;54:199214. 7. Bjrge T, Stocks T, Lukanova A, et al. Metabolic syndrome and endometrial carcinoma. Am J Epidemiol 2010;171:892902. 8. Creasman WT, Odicino F, Maisonneuve P, et al. Carcinoma of the corpus uteri. J Epidemiol Biostat 2001;6:4786. 9. Dimitraki M, Tsikouras P, Bouchlariotou S, et al. Clinical evaluation of women with PMB. Is it always necessary an endometrial biopsy to be performed? A review of the literature. Arch Gynecol Obstet 2011;283:261266. 10. Rodriguez GC, Yaqub N, King ME. A comparison of the Pipelle device and the Vabra aspirator as measured by endometrial denudation in hysterectomy specimens: the Pipelle device samples significantly less of the endometrial surface than the Vabra aspirator. Am J Obstet Gynecol 1993;168:5559. 11. Dijkhuizen FP, Mol BW, Brolmann HA, Heintz AP. The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia: a meta-analysis. Cancer 2000;89:17651772. 12. Clark TJ, Voit D, Gupta JK, Hyde C, Song F, Khan KS. Accuracy of hysteroscopy in the diagnosis of endometrial cancer and hyperplasia: a systematic quantitative review. JAMA 2002;288:16101621. 13. Polyzos NP, Mauri D, Tsioras S, Messini CI, Valachis A, Messinis IE. Intraperitoneal dissemination of endometrial cancer cells after hysteroscopy: a systematic review and meta-analysis. Int J Gynecol Cancer 2010;20:261267. 14. Chang YN, Zhang Y, Wang YJ, Wang LP, Duan H. Effect of hysteroscopy on the peritoneal dissemination of endometrial cancer cells: a meta-analysis. Fertil Steril 2011;96:957961. 15. Langer RD, Pierce JJ, OHanlan KA, et al. Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. Postmenopausal Estrogen/ Progestin Interventions Trial. N Engl J Med 1997;337:17921978. 16. Gull B, Carlsson SA, Karlsson B, Ylstalo P, Milsom I, Granberg S. Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding: is it always necessary to perform an endometrial biopsy? Am J Obstet Gynecol 2000;182:509515. 17. Lee JH, Dubinsky T, Andreotti RF, et al. ACR appropriateness Criteria pretreatment evaluation and follow-up of endometrial cancer of the uterus. Ultrasound Q 2011;27:139145. 18. Kitajima K, Murakami K, Yamasaki E, Kaji Y, Sugimura K. Accuracy of integrated FDG-PET/ contrast-enhanced CT in detecting pelvic and paraaortic lymph node metastasis in patients with uterine cancer. Eur Radiol 2009;19:1529 1536. A complete list of references is available on request to the editorial office.
CME Questions
This continuing medical education service is brought to you by the Medical Progress Institute, an This continuing medical education service is brought to you by the Medical Progress Institute, an institute institute dedicated to CME learning. Read the article Endometrial Carcinoma and answer the dedicated to CME learning. Read the article Endometrial Carcinoma and answer the following questions. following questions. This JPOG article has been accredited for CME by the Hong Kong College of Obstetricians and Gynaecologists. Answers are shown at the bottom of this page. We hope you enjoy learning with JPOG.
CME Article
Answer True or False to the questions below.
True 1. The risk factors for endometrial carcinoma (EC) include old age and obesity. 2. Ovarian function can be preserved during surgery. 3. Outpatient endometrial biopsy performs equally well when compared with dilatation and curettage under general anaesthesia. 4. Magnetic resonance imaging is preferred to compute tomography in the preoperative assessment of EC. 5. Lymphadenectomy is recommended and should always be performed for staging purposes. 6. Minimally invasive surgery is applicable for the treatment of EC. 7. Postoperative pelvic radiotherapy should be given to reduce recurrence and improve survival. 8. Chemotherapy is superior to radiotherapy after surgery in early-stage EC. 9. A combination of surgery, radiotherapy and chemotherapy is always needed for patients with advanced-stage EC. 10. The role of target therapy is not yet established for EC. False
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JAN/FEB 2013 jan/feb 2012 Vol. 39 38 No.

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Common Sleep Disorders in Children

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INTRODUCTION: SLEEP IS IMPORTANT IN CHILDREN

Table 1. Impact of poor/insufficient sleep and sleep-disordered breathing in children

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Figure 1. Sleep histogram.

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Figure 2. Spectrum of sleep-disordered breathing.

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