JPOG February 2013 HK

ISSN 1012-8875(HONG KONG)

Hong KongJAN/FEB 2012 Vol. 38 No. 1

JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY

Your partner in paediatric and O&G practice

JAN/FEB 2013 Vol. 39 No. 1 Your partner in paediatric and O&G practice

www.jpog.com

JOURNAL WATCH

PAEDIATRICS

Common Sleep Disorders in Children

OBSTETRICS

Bleeding Disorders in Pregnancy

Postpartum Pyrexia

CME ARTICLE

Endometrial Carcinoma

JAN/FEB 2013

Vol. 39 No. 1


Journal Watch

1 • TreatmentforCINandpretermbirth

• Fetalmacrosomiawithoutmaternaldiabetes:Effectoflowglycaemic indexdietinpregnancy

• Respiratoryratecorrectedforageandtemperatureindiagnosisof lowerrespiratoryinfectioninchildren

2 • LeukaemiaandbraintumourrisksfromchildhoodCTscans

• Paediatricventricularassistdeviceprolongssurvival

3 • Intermittentpreventivetreatmentformalariaininfancy:Noeffecton immunizationresponses

• StrictbloodglucosecontrolinICUafterpaediatriccardiacsurgery:No

benefit

• Effectivenessofrotavirusvaccinationinahigh-incomecountry

4 • Inhaledsteroidinchildhoodandadultheight

• Violenceagainsthandicappedchildren

• DTaPvaccineinUSA:Re-emergenceofpertussisafterfifthdose

Board Director, Paediatrics

Professor Pik-To CheungAssociate ProfessorDepartment of Paediatrics and Adolescent MedicineThe University of Hong Kong

Board Director, Obstetrics and Gynaecology

Professor Pak-Chung HoHead, Department of Obstetrics and GynaecologyThe University of Hong Kong

Editorial Board Professor Biran AffandiUniversity of Indonesia

Dr Karen Kar-Loen ChanThe University of Hong Kong

Associate Professor Oh Moh ChayKK Women’s and Children’s Hospital, Singapore

Associate Professor Anette JacobsenKK Women’s and Children’s Hospital, Singapore

Professor Rahman JamalUniversiti Kebangsaan Malaysia

Dato’ Dr Ravindran JegasothyHospital Kuala Lumpur, Malaysia

Associate Professor Kenneth KwekKK Women’s and Children’s Hospital, Singapore

Dr Siu-Keung LamKwong Wah Hospital, Hong Kong

Professor Terence LaoChinese University of Hong Kong

Dr Kwok-Yin LeungThe University of Hong Kong

Dr Tak-Yeung LeungChinese University of Hong Kong

Professor Tzou-Yien LinChang Gung University, Taiwan

Professor Somsak LolekhaRamathibodi Hospital, Thailand

Professor Lucy Chai-See LumUniversity of Malaya, Malaysia

Professor SC NgNational University of Singapore

Professor Hextan Yuen-Sheung NganThe University of Hong Kong

Professor Carmencita D PadillaUniversity of the Philippines Manila

Professor Seng-Hock QuakNational University of Singapore

Dr Tatang Kustiman SamsiUniversity of Tarumanagara, Indonesia

Professor Perla D Santos OcampoUniversity of the Philippines

Associate Professor Alex SiaKK Women’s and Children’s Hospital, Singapore

Dr Raman SubramaniamFetal Medicine and Gynaecology Centre, Malaysia

Professor Walfrido W Sumpaico MCU-DFT Medical Foundation, Philippines

Professor Cheng Lim TanKK Women’s and Children’s Hospital, Singapore

Associate Professor Kok Hian TanKK Women’s and Children’s Hospital, Singapore

Dr Surasak TaneepanichskulChulalongkorn University, Thailand

Professor Eng-Hseon TayThomson Women’s Cancer Centre, Singapore

Professor PC WongNational University of Singapore

Dr George SH YeoKK Women’s and Children’s Hospital, Singapore

Professor Hui-Kim YapNational University of Singapore

Professor Tsu-Fuh YehChina Medical University, Taiwan

1

3

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PRINT • ONLINE • DIGITAL EDITION

Download Medical Tribune Digital Edition

Go to www.medicaltribune.com orScan the QR code to download now!

December 2012

Elvira Manzano

Smoking nearly triples the risk of pre-mature death in women and quit-ting 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 smok-ing, 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, 1.91-2.04). [Lancet 2012.DOI.org/10.1016/S0140-6736(12)61720-6]

What was encouraging, however, was the positive effect that quitting seemed to have on women’s 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 mid-dle-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 never-smokers.” 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.

By 2011, 66,000 had died. Compared with non-smokers, smokers lost at least 10 years of life and died from smoking-related dis-eases such as lung cancer, heart disease and stroke. While the absolute hazards of pro-longed 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 smoker’s excess mortality in later middle age,” the authors said. The benefits are, how-ever, greater in those who quit earlier.

In a linked comment, Dr. Rachel Hux-ley, from the University of Minnesota, Min-neapolis, US, and Dr. Mark Woodward, from the University of Sydney, Australia, welcomed the findings. “Aside from its im-

pressive sample size, the Million Women Study is distinct from previous large co-horts—and 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 contin-ued smoking, many stopped before age 30 or 40 years.”

The results emphasize the need for ef-fective sex-specific and culturally-specific tobacco control policies that encourage adult smokers to quit and discourage chil-dren and young adults from starting smok-ing, they concluded.

Important benefits for women who quit smoking early

Women who quit smoking early can avoid a three-fold increased risk of death, according to the Million Women Study.

Turn to page 2 >>

Smart Rx. Every Time.

www.MIMS.com

FORUM

02Science and health policy: Lost in translation

COnFeRenCe

11Monoclonal antibody aids statin-refractory patients

philippine FOCUs

03DOH releases advisory on stem cell therapies

AFTeR hOURs

18Malacca: A journey through time

Rajesh Kumar

Daily multivitamin use for more than a decade caused a modest but statisti-

cally significant 8 percent reduction in all cancers among men in a large randomized, double-blind, placebo control trial.

Researchers analyzed data from the Phy-sicians’ 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

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 pros-tate cancer and 210 cases of colorectal can-cer, 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, respec-tively, 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 re-duction 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 reduc-tion in their total cancer risk but this was not any different from the case of healthier men.

Multivitamins may protect against cancer

www.medicaltribune.com

ReadMedical Tribune

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JAN/FEB 2013

Vol. 39 No. 1


Enquiries and Correspondence

5

JPOG JAN/FEB 2013 • ii

Publisher Ben YeoPublication Manager Marisa LamManaging EditorGreg TownAssociate Editor Grace LingDesignersAgnes Chieng, Sam ShumProduction Edwin Yu, Ho Wai Hung, Steven Cheung Circulation Christine ChokAccounting Manager Minty KwanAdvertising CoordinatorJenny Lim

Published by: UBM Medica Pacific Limited27th Floor, OTB Building160 Gloucester Road, Wan Chai, Hong KongTel: (852) 2559 5888 Email: [email protected]

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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Review ArticlePaediatrics

5 CommonSleepDisordersinChildren—DiagnosisandManagement

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 ArticleObstetrics

15 BleedingDisordersinPregnancy

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

15


From the research bench to your patient’s 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.

JPOG is Now CME-Accredited...

in Hong Kong, Indonesia, Malaysia and Singapore

For over 35 years, JPOG has been the only regional, peer-reviewed

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journal is proud to announce its CME-accreditation in the following

Asian countries: HONG KONG, INDONESIA, MALAYSIA

and SINGAPORE.

JAN/FEB 2013

Vol. 39 No. 1

The Journal of Paediatrics, Obstetrics and Gynaecology contains articles under licence from UBM Media LLC. The articles appearing on pages 49–53, and pages 67–80 are reprinted with permission of Consultant for Pediatricians. Copyright © 2011 UBM Media LLC. All rights reserved.


JPOG JAN/FEB 2013 • iii

ReviewArticlesComprehensive reviews providing the latest clinical information on all aspects of the management of medical conditions affecting children and women.

CaseStudiesInteresting cases seen in general practice and their management.

PictorialMedicineVignettes of illustrated cases with clinical photographs.

For more information, please refer to the Instructions for Authors on our website www.jpog.com, or contact:The EditorUBM Medica Asia Pte Ltd, 6 Shenton Way, #15-08 Tower 2, Singapore 068809Tel: (65) 6290 7400 Fax: (65) 6290 7401 E-mail: [email protected]

Review ArticleObstetrics

28 PostpartumPyrexia

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

Continuing Medical Education

37 EndometrialCarcinoma

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

Lisa Low, Illustrator

The Cover:Common Sleep Disorders in Children

© 2013 UBM Medica

37

28

HongKong


Journal Watch

JPOG JAN/FEB 2013 • 1

PEER REVIEWED

OBSTETRICS

Treatment for CIN and preterm birth

A study at 12 National Health Service hospitals in

England has suggested that any increase in prema-

ture delivery among women undergoing colposcopy

and biopsy or treatment for cervical intraepithelial

neoplasia (CIN) may be a result of statistical con-

founding.

The retrospective–prospective study includ-

ed 44,210 women who had had a cervical biopsy

at colposcopy during 1987–2009 with follow-up

data for up to 10 years. There were 18,441 single-

ton births at between 20 and 43 weeks of gesta-

tion. 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 ad-

justment 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

‘quality-managed’ colposcopy clinics.

The apparent increase in risk of preterm de-

livery after colposcopy and biopsy or treatment for

CIN may be due to confounding.

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).

Fetal macrosomia without maternal diabetes: Effect of low glycaemic index diet in pregnancy

Fetal macrosomia is often associated with mater-

nal 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 fe-

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 dur-

ing 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).

Respiratory rate corrected for age and temperature in diagnosis of lower respiratory infection in children Respiratory rate is important in the diagnosis of

lower respiratory tract infection in children, but it

may be affected by age and body temperature. Data

from a single children’s emergency department in

the Netherlands have been used to derive age- and

temperature-dependent reference values for respi-

ratory 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 chil-

dren 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 1°C rise in body tem-

perature. Respiratory rate values above the 97th

centile on the new age- and temperature-depen-

dent 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 37.0°C

to 37.9°C and 75 breaths/min with a temperature

of 39.0°C to 39.9°C. At ages 5 to 16 years the cor-

responding values were 36 and 44 breaths/min.

Centile charts for respiratory rate taking into

account age and body temperature may be useful

PAEDIATRICS

JPOG_JanFeb_2013_Final_COMBINE.indd 1 1/21/13 9:09 AM


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)

Leukaemia and brain tumour risks from childhood CT scans

Children are more sensitive to radiation than

adults, and it is important to keep radiation ex-

posure 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 be-

tween 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

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 af-

ter 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

of 30 mGy or greater increased the leukaemia risk

by a factor of 3.18 and a cumulative brain dose of

50–74 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: 499–505; Einstein AJ. Beyond the bombs: cancer risks of low-dose medical radiation. Ibid: 455–457 (comment).

Paediatric ventricular assist device prolongs survival

Heart failure is much less common in children than

in adults but carries a poor prognosis. Heart trans-

plantation in children is effective (83% survival

at 3 years), but a paucity of donor hearts means

a high waiting list mortality. Extracorporeal mem-

brane means a high waiting list mortality. Extracor-

poreal membrane oxygenation (ECMO) may be used

to keep some children alive until transplantation,

but it can be used for only 10–20 days, which is

not long enough for many children. Researchers in

North America have reported the use of a ventricu-

lar assist device as a bridge to heart transplanta-

tion in children. The EXCOR Pediatric Ventricular

Assist Device (Berlin Heart GmbH, Berlin, Germany)

has been assessed in a multicentre, single-group

study.

The study included 48 children up to the age

of 16 years in two groups according to body surface

area (< 0.7 m2 or 0.7 to < 1.5 m2) with 24 in each

group. Survival was compared with that of propen-

sity score–matched historical control groups who

underwent ECMO as a bridge to heart transplan-

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 in-

creased survival times.

Fraser CD et al. Prospective trial of a pediatric ventricular assist device. NEJM 2012; 367: 532–541; Addonizio LJ. Pediatric ventricular assist devices – first steps for babies. Ibid: 576–578 (editorial).


Journal Watch


PEER REVIEWEDPEER REVIEWED

Intermittent preventive treat-ment for malaria in infancy: No effect on immunization responses

Intermittent preventive treatment during infancy

(IPTi) with sulfadoxine–pyrimethamine has been

shown to reduce the incidence of clinical malaria in

infancy in countries with moderate or high malaria

transmission. IPTi is given at 8–10 weeks, 12–14

weeks, and 9 months at times of routine vaccina-

tion (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 sero-

logical responses to vaccinations.

A subset of 1,904 infants, out of 8,416 in-

fants 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 sulfadox-

ine–pyrimethamine for IPTi did not affect the re-

sults. Serological response data for other vaccina-

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: 1208–1219; Kavanagh BP. Glucose in the ICU-evidence, guidelines and outcomes. Ibid: 1259–1260 (editorial).

Effectiveness of rotavirus vacci-nation in a high-income country

Reports of the effectiveness of rotavirus vaccina-

tion 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 reaction–confirmed rotavirus gastroenteritis

and 276 age- and hospital-matched controls, all

from a random sample of 39 Belgian hospitals be-

tween February 2008 and June 2012. The effective-

ness of two doses of monovalent rotavirus vaccine

tions were available for 2,396 children, and IPTi did

not reduce responses.

IPTi does not impair responses to routine im-

munizations in infancy. Lancet commentators point

out that there is uncertainty whether IPTi is asso-

ciated 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: 1001–1010; Benn CS, Aaby P. Does IPTi decrease malaria morbidity but not mortality? Ibid: 958–960 (comment).

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 glu-

cose control might provide some advantages, but

there is concern about insulin-induced hypoglycae-

mia. A trial in two US cardiac intensive care units

(ICUs) has shown a low rate of severe hypoglycae-

mia with carefully monitored intensive glucose

control but no clinical benefits.

The trial included 980 children aged 0–36

months recovering from cardiac surgery with car-

diopulmonary bypass in ICUs in Boston, Massachu-

setts, 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 pe-

riod). The rate of severe hypoglycaemia in the tight

control group was 3%. The rates of health-care-

associated infection on the ICU was 8.6% (tight



was 90% overall, 91% among children aged 3–11

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).

Inhaled steroid in childhood and adult height

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 Pro-

gram (CAMP) trial, a total of 1,041 children aged

pared with other children, children with a disability

were almost four times more likely to suffer vio-

lence 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 preva-

lence 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: 899–907; Lund EM, Vaughn-Jensen JE. Victimisation of children with disabilities. Ibid: 867–869 (comment).

DTaP vaccine in USA: Re-emergence 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 15–18 months and at 4–6

years. Despite this, there has been a resurgence

of whopping cough and the duration of protection

after the fifth dose has been questioned. Now, a

report from California has suggested that protec-

tion deteriorates quite rapidly.

The study, in the Kaiser Permanente organi-

zation, included children who had been fully vac-

cinated 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 in-

creased 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: 1012–1019.

5–13 years with mild-to-moderate asthma were

randomized to inhaled budesonide 200 µg twice

daily, inhaled nedocromil 8 mg twice daily, or pla-

cebo, for 4–6 years. The adult height of 943 par-

ticipants (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 dif-

ference of 1.2 cm between the budesonide and

placebo groups was significant, but the 0.2 cm dif-

ference between nedocromil and placebo groups

was not. For each microgram per kilogram of body

weight increase in daily dose of budesonide in the

first 2 years of treatment, there was a 0.1 cm re-

duction 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 at-

tained 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: 904–912.

Violence against handicapped children

Child abuse is common. It is estimated that in 2001,

some 53,000 children were murdered and 223 mil-

lion 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 dis-

ability are particularly vulnerable to violence and is

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 preva-

lence 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-


The Changing PanoramaOf Women’s Health:

Navigating New Frontiers22-24 August 2013Visit www.Sicog2013.com for more details soon!

Imaging Paediatric Brain Tumours

Tang Phua Hwee, MBBS, FRCR, MMed Diagnostic Radiology

PAEDIATRICS I PEER REVIEWED


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 light–dark 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 activ-

ity, 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 develop-

mental changes that take place when one ages through the years.

PAEDIATRICS I PEER REVIEWED

Common Sleep

Disorders in Children—

Diagnosis and ManagementPetrina 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



PAEDIATRICSPAEDIATRICS I PEER REVIEWED

The cycling of NREM and REM sleep is estab-

lished by 3 to 4 months of age. Sleep usually be-

gins in NREM sleep and progresses through deeper

NREM sleep stages (N2 and N3) before the first epi-

sode 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 pe-

riod of between 50 to 70 minutes in infants to 90

to 120 minutes in adults. Stage N3—also 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 re-

quired 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. Day–night

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 tod-

dler.

• At3to5yearsold, most children do away with

naps and sleep an average duration of 11–12

hours.

• School-goingchildren require about 10 to 11

hours of sleep.

• Adolescents tend to have irregular sleep

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 cir-

cadian rhythm, leading to a natural tendency to

sleep late and, therefore, rise late.

Good Sleep Hygiene Advice for Children

• Keepconsistentsleepandwaketimesdaily,in-

cluding over the weekends.

• Do not use the bed for any activity other than

sleeping (eg, watching television, playing, eat-

ing). Avoid placing the computer, television,

mobile phones, and other personal electronic

devices in the bedroom.

• Donotuse thebedroomfor time-outorpunish-

ment.

• The child’s bedroom should be conducive for

sleeping at bedtime—cool, quiet, and comfort-

able. 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

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

Daytime somnolence Reduced immune functionImpaired memory and concentration

Increased risk of obesity/ metabolic conditions

Impaired motor skills Cardiopulmonary complications Poor academic performance Poor growthMood disturbances (mood lability, poor emotional control, irritability)

Disruptive behaviour (aggressiveness, impulsivity, hyperactivity)

Negative parent–child relationships




activities before sleep, such as watching excit-

ing 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,likeatoy,blanketordoll,

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.2–4 These figures may even be an underes-

timate, as many parents do not voice their concerns

about their child’s sleeping habits unless asked.

It is therefore vital for all physicians managing

the paediatric population to be vigilant in screen-

ing 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 hyper-

activity disorder).

A screening tool that has been used widely to

Figure 1. Sleep histogram.




identify major sleep disorders in the paediatric pop-

ulation 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 = exces-

sive daytime sleepiness, A = awakenings during the

night, R = regularity and duration of sleep, and S =

snoring.1

In this article, we will discuss paediatric in-

somnias, sleep-related breathing disorders, circa-

dian 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, obstruc-

tive sleep apnoea [OSA], eczema, allergic rhinitis,

asthma), psychological conditions (eg, stress, anxi-

ety), 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

child–parent 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 return-

ing to sleep following an awakening.

The child’s bedroom should be conducive for sleeping at bedtime.




Epidemiology. Onset is usually at 4 to 6

months old, and it has been estimated to affect

25–50% of infants at 6–12 months old and 15–20%

of toddlers.1

Presentation. It is normal for infants to wake

intermittently in the night, but when they are un-

able to return to sleep without external factors like

parental presence or rocking, recurrent or prolonged

night awakenings can result.5 Persistent night

awakenings can continue up to mid-childhood, but

the negative sleep associations developed during

infancy tend to taper off with age (eg, pacifier us-

age till 3 to 4 years old, parental help to fall asleep

till 6–7 years old).

Risk factors. Factors that may increase the

likelihood of night awakenings include breastfeed-

ing, co-sleeping, colic, intercurrent illness, parental

anxiety, and when the child has achieved new mo-

tor/social milestones (eg, pulling to stand, separa-

tion 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 ‘self-

soothing’.

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 in-

dependently 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 ex-

tinction’, and ‘fading’ have been used widely. Ex-

tinction involves the parent putting the child to bed

at a fixed time and ignoring the child’s cries com-

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 physi-

cally distances himself/herself from the child each

night, such that the eventual aim is to have the

parent outside the child’s room.

Parents–child interaction is a very important

influencing factor in a child’s sleeping behaviour,

and there is no one best method for every family.

Any change would require consistency and perse-

verance of the caregiver(s) to work.

Limit-setting Sleep Disorder

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 con-

tinue 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




emphasized more. The method of bedtime fading

may be practised, in which the bedtime is gradu-

ally 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.

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 perfor-

mance.

Risk factors . Exact pathophys io log ica l

mechanisms remain largely unknown. Up to 40% of

patients have a positive family history, and poly-

morphisms in the clock gene PER3 have been de-

scribed.6

Management. Polysomnography is not rou-

tinely indicated unless there are symptoms sugges-

tive of sleep-disordered breathing. Sleep logs are

useful to demonstrate the habitually late sleep on-

set and late awakening.6 Catch-up sleep on week-

ends should be documented as well.

The main aim of management is to gradually

adjust the sleep/wake schedule such that the typi-

cal 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 expo-

sure to bright light late at night. Success has been

shown to be largely dependent on patient and en-

vironmental factors (such as patient and parental

motivation).

SLEEP-RELATED BREATHING DISORDERS

Sleep-related breathing disorders describe a spec-

trum 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, hy-

poxaemia, or hypercarbia, and with no associated

sleep disturbance or associated daytime symptoms.

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




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 air-

way obstruction (obstructive hypoventilation) and/

or intermittent complete or partial obstruction (ap-

noea/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 popula-

tion in the 1970s, but newer studies have estimated

the incidence to be 2–3% in children below the age

of 10 years.10 There is a familial tendency, but the

relative role of genetics versus environmental fac-

tors has yet to be determined.

The peak age is between 4 to 7 years old,

usually in children with enlarged tonsils and/or ad-

enoids. 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 chil-

dren 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 subject’s 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 up-

per airway obstruction, while in children with neu-

romuscular disease like cerebral palsy, obstruction

is caused by abnormal muscle tone. Children with

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, espe-

cially 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 un-

noticed 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 desatura-

tions, arousals, and sleep fragmentation.10 The se-

cretion 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 complica-

tions (pulmonary hypertension, cor pulmonale) and

metabolic conditions (insulin resistance, impaired

Table 2. Symptoms of obstructive sleep apnoea

Sleep symptoms Wake symptoms

SnoringApnoeasSnortingGaspingParadoxical breathingEnuresisRestless sleepFrequent arousalsUnusual body positions

Poor school performance Aggression Hyperactive behaviour Inattention Excessive daytime sleepiness Morning headaches




glucose tolerance, hypertension) may arise if OSA

is untreated or, rarely, even death can occur in se-

vere 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 differenti-

ate a primary snorer from a child with OSA. An over-

night polysomnography is the gold standard test

and involves continuous monitoring and recording

of the child’s sleep and breathing parameters. The

aim is to look for sleep disruption, laboured breath-

ing, airflow limitation or cessation, hypoxaemia, and

hypercarbia.

Treatment. In 2002, the American Acad-

emy of Pediatrics issued an evidence-based

clinical practice guideline with recommenda-

tions for the management of OSA in children.12

Adenotonsillectomy is curative in most children,

and postoperatively, repeat polysomnograms may

be done in some to document resolution. Continu-

ous 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.

PARASOMNIAS

Parasomnias are sleep-related phenomena that dis-

rupt 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 Para-

somnias can generate great anxiety as some can be

very bizarre and even violent, causing much distress

to the caregivers.

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 5–15%, 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 dur-

ing the initial third of the sleep period.

Epidemiology. An estimated 15–40% of all

children will sleepwalk on at least one occasion,

with only 3–4 % having frequent episodes that oc-

cur weekly to monthly. Peak age is usually between

4 to 8 years old. The majority settle by adolescence,

Clinical history

and physical

examination cannot

always differentiate

a primary snorer

from a child

with OSA.




Key points

• 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.

and a significant familial pattern is associated.

Sleepwalking can commonly co-occur with sleep-

talking and night terrors.14

Presentation. Episodes often begin with sit-

ting 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 epi-

sode and would appear confused and disorientated if

awakened.

Night Terrors

Night terrors also transpire during the SWS cycle,

in the first third of sleep.

Epidemiology. Typical onset is in early child-

hood 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 depriva-

tion (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

Nightmare Disorders

These attacks, as opposed to the conditions men-

tioned 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 in-

tensely disturbing dream mentation, usually in-

volving 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.




Management is based on reassurance and edu-

cation, 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 door-

knob of the child’s 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.

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):B38–B52.3. Mindell JA. Sleep disorders in children. Health Psychol 1993;12:151–162.4. Owens JA, Spirito A, McGuinn M, Nobile C. Sleep habits and sleep disturbances in elemen-tary school-aged children. J Dev Behav Pediatr 2000;21:27–36.5. 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;90:554–560.7. Bhargava S. Diagnosis and management of common sleep problems in children. Pediatr Rev 2011;32:91–98.8. Glaze DG. Childhood insomnia: why Chris can’t sleep. Pediatr Clin North Am 2004;51:33–50. 9. Spicuzza L, Leonardi S, La Rosa M. Pediat-ric sleep apnea: early onset of the ‘syndrome’? Sleep Med Rev 2009;13:111–122.10. American Thoracic Society. Standards and indications for cardiopulmonary sleep stud-ies in children. Am J Respir Crit Care Med 1996;153:866–878.11. Urquhart D, Montague ML. When to remove tonsils and the alternatives. Paediatrics & Child Health 2012;22:37–41.12. Peppard, PE, Young,T, Palta, M et al. Lon-gitudinal study of moderate weight change and sleep-disordered breathing. JAMA

2000;284:3015–3021.13. American Academy of Pediatrics. Clinical practice guideline: diagnosis and management of childhood obstructive sleep apnoea syn-drome. Pediatrics 2002;109:704–712. 14. Sheldon SH. Parasomnias in childhood. Pediatr Clin North Am 2004;51:69–88.15. 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;106:67–74.17. Chokroverty S, Hening WA, Walters AS. An approach to the patient with movement disor-ders during sleep. In: Chokroverty S, Hening WA, Walters AS, eds. Sleep and Movement Disorders. Philadelphia: Butterworth Heine-mann; 2003:265–272.

18. Rosen G, Mahowald MW, Ferber R. Sleep-walking, 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; 1995:99–106.19. Kales JD, Kales A, Soldatos CR, Chamber-lin K, Martin ED. Sleepwalking and night ter-rors related to febrile illness. Am J Psychiatr 1979;136:1214–1215.20. Owens JA, Millman RP, Spirito A. Sleep ter-rors in a 5-year-old girl. Arch Pediatr Adolesc Med 1999;153:309–312.21. Mahowald MW. Arousal and sleep-wake transition parasomnias. In: Lee-Chiong TL, Sateia MJ, Carskadon MA, eds. Sleep Medicine. Philadelphia: Hanley & Belfus; 2002:207–213.22. Guilleminault C, Palombini L, Pelayo R, Chervin RD. Sleepwalking and sleep terrors in prepubertal children: what triggers them? Pedi-atrics 2003;111:e17– e25.

Acknowledgement

This paper was made possible through a collaboration between KK Women’s and Children’s 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.

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 disor-

ders are prevalent in the different age groups,

but for all children, poor/insufficient sleep and

sleep-disordered breathing can have mild to seri-

ous sequelae.

Screening for sleep disorders for all children

should be part of routine health care, with onward

referral to a paediatric sleep specialist for sympto-

matic, complex, or high-risk patients.

About the AuthorsDr 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 Women’s and Children’s Hospital, Singapore.

REFERENCES


Perinatal Case Management—Caring for Mothers as They Care

for BabiesCh’ng Ying Chia, MA (Applied Social Studies); Jemie Biwen Wang, Bachelor of Psychology (Hons);

Helen Chen, MBBS, M Med (Psych), Dip. Psychotherapy

OBSTETRICS I PEER REVIEWED


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 im-

prove 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 PAI-

1 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 7–10% of pregnan-

cies (Table 2). The most common causes are gestational thrombocytopenia (GT) (75%),

15–20% are due to thrombotic microangiopathies when secondary to hypertensive dis-

orders, 3–4% due to immune causes (3%) and other rare causes include constitutional

thrombocytopenias, infection and malignancy (< 1%).

Bleeding Disorders in Pregnancy

Eleftheria Lefkou, MD, PHD; Beverley J Hunt, MB, FRCP, FRCPath, MD





Table 1. Bleeding disorders

PlateletsThrombocytopenia • Failure of production • Decreased megakaryocyte mass – radiation, chemicals, drugs; intrinsic bone

marrow abnormalities (aplastic anaemia, leukaemia, myelofibrosis, myelo-dysplastic syndrome, etc); replacement of bone marrow with carcinoma cells (plasma cells, etc)

• Ineffective thrombopoiesis – megaloblastic anaemias (B12, folic acid deficiency) • Increased destruction • Immune mechanisms: autoimmune thrombocytopenic purpura; autoimmune

diseases (lupus erythematosus) • Splenomegaly (usually secondary to liver disease)

• Pregnancy directly related • Microangiopathies (pre-eclampsia, HELLP, disseminated intravascular coagula-tion, thrombotic thrombocytopenic purpura)

• Acute fatty liverDilutional/uncertain • Gestational thrombocytopenia

• Human immunodeficiency virusPlatelet dysfunction • Hereditary • Disorders of platelet adhesion (Bernard–Soulier 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)

• Acquired • Drugs – aspirin and other non-steroidal anti-inflammatory drugs; alcohol, anti-biotics (carbenicillin, penicillin, moxalactam, third-generation cephalosporins)

• Other – uraemia, liver disease, heart bypass surgery, haematological malignan-cies, myeloproliferative disorders, leukaemia, etc

Vessel wall • Drugs (chronic glucocor-

ticoid use, penicillins, sulphonamides)

• Vitamin C deficiency • Paraproteinaemia • Henoch–Schönlein purpura

and other vasculitis • Hereditary defects • Hereditary haemorrhagic telangiectasia

• Ehlers–Danlos syndrome

Coagulation • Acquired causes • Vitamin K antagonism/deficiency

• Liver disease • Anticoagulation therapy • Disseminated intravascular coagulation • Factor inhibitors

• Inherited causes • Factor deficiencies (von Willebrand disease, haemophilia A and B, rare – FXI, FVII, FX, prothrombin deficiency, fibrinogen deficiency/dysfunction)




Gestational Thrombocytopenia

The platelet count in pregnancy is lower than the

non-pregnant state. In 5–8% of all pregnancies, the

platelet count at term is below the normal range

(150–400 × 109/L). In GT, platelet counts are typi-

cally > 70 × 109/L, with about two-thirds just below

the normal lower limit, eg, between 130 × 109/L and

150 × 109/L. It is exceptional for the platelet count

to fall below 80 × 109/L, but in rare cases, subse-

quently confirmed as GT, counts may be as low as

50 × 109/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,

against platelet surface glycoproteins, especially

Ib–IX and IIb–IIIa, causing their premature destruc-

tion by the reticuloendothelial system. ITP is com-

mon in haematology practice, with an incidence in

the general adult population of 6.6 per 100,000,

with 1–5 cases per 10,000 pregnancies. However, it

is around 100 times less common than GT in preg-

nancy. The majority of cases occur alone, but rarely

it can be associated with systemic lupus erythe-

matosus and human immunodeficiency virus, or is

secondary to drugs.

Due to the increased platelet turnover, the

residual platelets are young and more haemostati-

cally 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

Table 2. Causes of thrombocytopenia in pregnancy

Pregnancy-related Other

Gestational (or incidental, 75%)

Spurious (EDTA-induced platelet aggregation) send a citrate sample to exclude this

Pre-eclampsia Autoimmune (immune thrombocy-topenic purpura, drug-induced, systemic lupus erythematosus, antiphospholipid syndrome)

Haemolysis, elevated liver enzymes and low platelet (HELLP syndrome)

Viral, eg, human immunodeficiency virus, Epstein-Barr virus, cytomega-lovirus, von Willebrand type IIB disease

Disseminated intravascular coagulation

Haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura

Acute fatty liver Congenital/marrow disease/hyper-splenism/liver disease

Folate deficiency Drugs (not low-molecular-weight heparins)




been reported, and maternal morbidity is minimal

if appropriate therapy is administered during preg-

nancy and childbirth.

Usually the clinical problem is differentiating

GT from ITP (Table 3). This has minor clinical impor-

tance for the mother but is essential for the fetus

– owing to the transplacental passage of antibody,

ITP may rarely cause thrombocytopenia in the fetus;

GT does not. Neonatal thrombocytopenia occurs in

up to 14% of pregnancies complicated by ITP: 7.5%

have severe thrombocytopenia with platelet counts

< 50 × 109/L, although only 4% have platelet counts

< 20 × 109/L, and are therefore at risk for haemor-

rhage at birth. Splenectomy prior to pregnancy is

the only recognized risk factor associated with the

development of neonatal thrombocytopenia. This

may be due to the fact that splenectomized women

usually have more severe ITP and large amounts of

circulating autoantibodies. The main concern for

the newborn during the labour is trauma-provoking

neonatal cerebral haemorrhage.

The British Society of Haematology recom-

mends that all women with platelet counts less

than 100 × 109/L should be screened for clinical or

laboratory evidence of pre-eclampsia, coagulopa-

thy or autoimmune disease. Bone marrow exami-

nation 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 > 20–30

× 109/L do not need treatment until the third trimes-

ter unless there is also a defect in platelet function

or abnormal coagulation. Routine platelet counting

may underestimate the total count, for most analyz-

ers count platelets according to a size range. How-

ever, 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

platelet counting based on light scatter.

From 35 to 36 weeks, it is usual to give treat-

ment to raise the platelet count to at least 50 ×

109/L for normal vaginal delivery and caesarean

section. Concerns over the risk of haematoma for-

mation and neurological damage have led to rec-

ommendations that spinal or epidural anaesthesia

not be performed unless the platelet count is > 80

× 109/L. This recommendation is based on consen-

sus rather than evidence. Thromboelastogram data

would suggest that lower levels of thrombocytope-

nia might be tolerated. There is no evidence that

the bleeding time predicts the risk of haemorrhage

in this situation.

Current recommendations for the mode of

delivery do not support caesarean section being a

safer option for the fetus, except for obstetric indi-

cations. The use of vacuum extraction and compli-

cated instrumental delivery is contraindicated, as

are the use of scalp electrodes for monitoring the

labour.

Specific Treatments for ITP

The main treatment options for maternal ITP are

corticosteroids or intravenous immunoglobulin

Table 3. Distinguishing immune thrombocytopenic purpura (ITP) from gestational thrombocytopenia (GT)

GT ITP

Time of presentation > Second trimester From first trimester

Platelet count > 70–80 × 109 More severe

Neonatal thrombocy-topenia

No Possible

Resolution after delivery Yes No/yes

Platelet size Normal Normal/big

Antiplatelet antibodies No/yes No/yes




(IVIg). Vinca alkaloids, androgens and most immu-

nosuppressive drugs should not be used in preg-

nancy, however azathioprine is safe.

• Steroids. The British Society of Haematology

guidelines recommend 1 mg/kg but in our ex-

perience a dosage of 10–20 mg may be effec-

tive 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 pla-

centa, 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-

ter.

• Intravenousimmunoglobulin. IVIg (usual

prescription, 0.4 mg/kg/d for 3–5 days) has

a similar response rate as in the non-pregnant

woman; however, duration of response is short,

usually lasting 2–3 weeks, and repeated infu-

sions may be required. Currently, there is an

international shortage of IVIg preparations.

• Anti-D. This is given to rhesus-positive pa-

tients in whom red cells coated in antibody

block the reticuloendothelial system, prevent-

ing platelet destruction. It is currently unavail-

able in the UK, and experience in pregnancy

has been limited. Some studies have admin-

istered intravenous anti-D daily for 5 days;

others a single dose lasting < 5 minutes. In

a trial, eight women were treated in the se-

cond 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. Ideal-

Gestational thrombocytopenia does not require treatment in pregnancy and resolves spontaneously after delivery.




ly, this should be performed in the second tri-

mester.

• Life-threateningbleedinginasevereref-

ractoryITP may respond to high-dose intrave-

nous methyl prednisolone and intravenous IVIg.

This needs to be managed by an expert.

{ Rituximab. There is limited data about

the use of CD20 monoclonal antibody in

pregnancy. The manufacturers recom-

mend abstaining from pregnancy during

and for 12 months after its use. Ritux-

imab 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 preg-

nancy, and animal studies have shown

evidence of fetal abnormality. The manu-

facturers of both eltrombopag and romip-

lostim 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 throm-

bocytopenia 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 incom-

patibility, analogous to that in rhesus haemolytic

disease, with maternal antiplatelet IgG antibodies

crossing the placenta and destroying fetal platelets.

The foreign fetal platelet antigens are inherited

from the father. The majority of cases are caused by

antibodies directed against human platelet antigen

(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 haem-

orrhage (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 neo-

nate, excessive haematoma at injection sites, and

postnatal ICH. NAIT should be diagnosed after the

exclusion of sepsis, necrotizing enterocolitis, dis-

seminated intravascular coagulation (DIC), placen-

tal insufficiency, congenital infection, asphyxia,

and artefact. Samples of the mother’s and new-

born’s blood should be sent to the Blood Transfu-

sion 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 possi-

ble to obtain fetal DNA from maternal blood and to

platelet-antigen type the fetus early in pregnancy

to assess whether the fetus of heterozygous fa-

ther is affected. Antenatal therapy in subsequent

pregnancies remains contentious, but in affected

fetuses options include intrauterine platelet trans-

fusion, maternal immunoglobulin and steroids, all

of which should be done at a specialized fetal medi-

cine centre.




If the newborn’s 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 24–48 hours, leaving a win-

dow of risk for ICH.

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 mi-

crovasculature. 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 guide-

lines for thrombocytopenia described above.

HELLP syndrome is a variant of pre-eclampsia

occurring in the second or third trimester of preg-

nancy, and presents occasionally post partum. It

complicates between 0.5% and 1% of pregnancies

and 10–20% 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

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 regula-

tion 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 recov-

ery within 24–48 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 intra-

uterine 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 microan-

giopathic 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, of-

ten intensive, therapy.

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation is a clinico-

pathological syndrome characterized by an uncon-

trolled systemic activation of coagulation leading

to microvascular deposition of fibrin, and thus to

consumption of coagulation factors, platelets, and

physiological anticoagulants. This produces a re-

duction in platelet count and in coagulation factors,

especially fibrinogen, and so prolongation of the

activated partial thromboplastin time and interna-

tional normalized ratio.

Obstetric causes of DIC include amniotic fluid




embolism, placental abruption, eclampsia or pre-

eclampsia, retained dead fetus, and septic abor-

tion. 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 situ-

ation is usually short-lived and self-limiting. The

pathogenic mechanism of DIC is usually the leak-

age of tissue factor–like material into the circula-

tion, 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 car-

diovascular collapse due to an allergic response to

amniotic fluid.

Management of DIC involves treating the

cause and replacing the missing haemostatic com-

ponents 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.

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is an

acute, rare and life-threatening disorder affecting

3–7 persons per million per annum. TTP is a clini-

cal diagnosis, characterized by the classic pentad

of thrombocytopenia, microangiopathic haemolytic

anaemia, fluctuating neurological signs, renal im-

pairment, and fever, often with insidious onset.

Neurological impairment has multiple manifesta-

tions including headache, bizarre behaviour, tran-

sient sensorimotor deficits, seizure, and coma.

Additional complications that may be seen include

gastrointestinal ischaemia (manifest as abdomi-

nal pain) and serous retinal detachment. How-

ever, some TTP patients do not have neurological

symptoms or signs at presentation, and fever and

renal impairments are present in only a minority of

patients. It is due to a deficiency of ADAMTS-13;

without this protein, spontaneous platelet aggre-

gates 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 con-

genital TTP.

The distinction of TTP from pregnancy-relat-

ed complications – pre-eclampsia, eclampsia and

HELLP syndrome – may be difficult. TTP is more

common in women than in men, with 12–25% of

cases diagnosed during pregnancy or post partum,

with 75% of episodes occurring around the time

of delivery. Routine investigations at presenta-

tion should include full blood count, film, clotting

screen, lactate dehydrogenase, direct antiglobulin

test, urea and electrolytes, liver function tests, and

urine dipstick for protein.

The management of acute TTP is with immedi-

ate plasma exchange and general supportive ther-

apy, including red cell exchange. Immediate treat-

ment is required, for delay can result in death due

to platelet aggregates causing myocardial infarc-

The distinction of TTP

from pregnancy-related

complications – pre-eclampsia,

eclampsia and HELLP syndrome

– may be difficult




tion, such deaths account for 1% of the UK mater-

nal 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 throm-

botic microangiopathy characterized by microan-

giopathic 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 re-

lease into the circulation of Shiga-like toxin after

an infection by Escherichia coli (O157:H7); or ‘atypi-

cal’, 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 disor-

ders, intramuscular injections, invasive monitoring

techniques, vacuum extraction and rotational/mid-

cavity 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 intrader-

mally or subcutaneously.

von Willebrand Disease

von Willebrand disease is the most common inherit-

ed bleeding disorder, affecting 1–3% 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, in-

creasing 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 (20–25%) 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 in-

creased 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, bleed-

ing after surgery and dental extraction, and a family

history. However, many women with mild vWD re-

main undiagnosed within the community. Questions

about near relatives’ bleeding history, especially at

the time of surgery, dentistry and childbirth, are es-

sential in history taking. One of the effects of preg-

nancy is to increase levels of vWF, so mothers with

type I vWD will not bleed antenatally. However, lev-

els 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 ab-




normal vWF for the patient’s platelet vWF recep-

tor, the glycoprotein Ib–IX complex. This leads to

subsequent platelet activation, aggregate forma-

tion, and clearance by the reticuloendothelial sys-

tem. 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 analy-

sis will show absence of high-molecular-weight

forms.

In type III vWF levels show little increment in

pregnancy, and these women require vWF concen-

trates. 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 proce-

dures 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 re-

quire prophylactic treatment for delivery. In women

with type II vWD, treatment is required for opera-

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

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 con-

sidered in the case of postpartum haemorrhage.

Haemophilias

Haemophilia A (factor VIII deficiency) and B (fac-

tor IX deficiency) are X-linked recessive disorders,

and affect approximately 1 in 10,000 male births.

At least 30% of newly diagnosed cases of haemo-

philia 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 Doc-

tors’ Organisation recommends that haemophilia

carriers should have their factor level checked at

booking and at 28 and 34 weeks’ gestation to al-

Table 4. Severity of haemophilia and clinical presentation

Severe < 1% FVIII Bleed spontaneously into joints and cavities

Moderate 2–5% FVIII Bruise badly and bleed +++ after surgery

Mild 5–40% FVIII Bruise badly and bleed +++ after surgery




low appropriate management of labour and delivery

and to assess the need for prophylactic treatment,

although supplementation is uncommonly required.

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 consid-

ered 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 ante-

natal care as this will be helpful in managing preg-

nancy and delivery. Fetal sexing can be performed

either by ultrasound examination at 18–20 weeks’

gestation or, ideally, by testing circulating cell-free

fetal DNA from maternal blood for Y chromosome–

specific sequences from the seventh week of gesta-

tion. For women wishing to avoid the miscarriage

risk associated with first-trimester prenatal diag-

nosis, 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 vag-

inal delivery. The option of elective caesarean sec-

tion in an attempt to reduce the risk of neonatal ICH

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

recommended treatment of choice in pregnant car-

riers 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 ef-

fects, including placental insufficiency, miscarriage

or preterm labour, and maternal and/or fetal hy-

ponatraemia, are rare. Desmopressin does not pass

into breast milk in significant amount.

Regional anaesthesia in carriers of haemophil-

ia 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 treat-

ment). It should be performed by an expert anaes-

thetist with the help of a specialized haematologist

for assessment of coagulation status and arrange-

ment 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 in-

cidence of 8%. Homozygotes are severely affected

with FXI levels of < 15 IU/dL while heterozygotes

Haemophilia carrier status

itself is not a contraindication

to vaginal delivery




Practice points

• 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 50–80 × 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 consid-ered, and haematological advice sought urgently

have partial deficiency with levels of 15–70 IU/dL

(normal range, 70–150 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 preg-

nancy and the puerperium.

Levels of FXI should be checked at booking, 28

and 34 weeks’ gestation, and prior to invasive pro-

cedures. In general, women with FXI levels < 15 IU/

dL have a 16–30% risk of excessive bleeding during

delivery, and should receive prophylactic FXI con-

centrate at the onset of labour or prior to planned

induction or caesarean section. Tranexamic acid 1 g

6–8 hourly should be considered post delivery and

for 3 days post partum, or 5 days following cae-

sarean section. FXI concentrates carry a thrombotic

risk, and so peak levels should not exceed 70 IU/

dL. More recently, recombinant FVIIa has been used

successfully in FXI deficiency.

Inherited Disorders of Fibrinogen

Genetic abnormalities of fibrinogen comprise quan-

titative abnormalities (afibrinogenaemia and hy-

pofibrinogenaemia) and qualitative abnormalities

(dysfibrinogenaemia and hypodysfibrinogenaemia).

Afibrinogenaemia is a rare disorder (affecting

1–2 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 rup-

ture 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-tri-

mester losses, but the majority are asymptomatic

(62%).

The management of bleeding episodes in afi-

brinogenaemia or dysfibrinogenaemic patients is

replacement of fibrinogen to a level of > 0.8 g/L,

which is usually adequate to maintain haemosta-

sis. Cryoprecipitate has been used as a source of

fibrinogen; each bag of cryoprecipitate contains

100–250 mg of fibrinogen, but plasma-derived fi-

brinogen concentrates are preferable, having had

virus inactivation and are licensed for this indica-

tion. The usual starting dose for adults is 1–2 g in-




travenously. In thrombotic events, patients receive

anticoagulation therapy. Recurrent spontaneous

first-trimester loss is prevented by regular fibrin-

ogen 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 1.0–1.5 g/L during the

procedure and for 4–14 days following surgery

should be given. Thromboprophylaxis should be

considered, especially in dysfibrinogenaemic pa-

tients.

Other Inherited Bleeding Disorders

Rare inherited bleeding disorders such as prothrom-

bin deficiency, FV, FII, FX and FXIII deficiencies, and

combined FV and FVIII deficiency should be man-

aged 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 1–4 months post partum and rarely

ante partum. Usually, the antibody disappears spon-

taneously after a few months. The clinical presenta-

tion is with prolonged bleeding, postpartum haem-

orrhage, menorrhagia, or soft tissue haematomas

with a prolonged activated partial thromboplastin

time. In contrast with inherited haemophilia, ac-

quired 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 preg-

nancy and the puerperium.

FURTHER READING

Birchall E, Murphy M, Kaplan C, Kroll H; on behalf of the Euro-pean Fetomaternal Alloimmune Thrombocytopenia Study Group. European collaborative study of the antenatal management of feto-maternal alloimmune thrombocyto-penia. Br J Haematol 2003;122:275–288.

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;120:574–596.

Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes following maternal exposure to rituximab. Blood 2011;117:1499–1506.

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;154:208–215.

Chi C, Lee CA, Shittagh N, Khan A, Pollard D, Kadir RA. Pregnancy in carriers of haemophilia. Haemophilia 2008;14:56–64.

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;21:859–869.

Hunt BJ, Thomas-Dewing RR, Bramham K, Lucas SB. Preventing maternal deaths due to acquired thrombotic thrombocy-topenic purpura. J Obstet Gynaecol Res 2013;39:347–50.

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;12:301–336.

Levi M. Disseminated intravascular coagulation (DIC) in pregnancy and the peri-partum period. Thromb Res 2009;123(suppl 2):S63–S64.

Michel M, Novoa M, Bussel J. Intravenous anti-D as treatment for immune thrombocytopenic purpura (ITP) during preg-nancy. Br J Haematol 2003;123:142–146.

Myers B. Diagnosis and management of maternal thrombocyto-penia in pregnancy. Br J Haematol 2012;158:3–15.

© 2012 Elsevier Ltd. Initially published in Obstetrics, Gynaecology and Reproductive Medicine 2012;22(12):339–346.

About the AuthorsEleftheria Lefkou is Consultant Haematologist, Blood Transfu-sion Unit, Hippokrateion University Hospital of Thessaloniki, Greece. Beverley J Hunt is Professor of Thrombosis & Haemo-stasis, King’s College, and a Consultant at the Department of Haematology, Lupus & Pathology, Guy’s & St Thomas’ NHS Foun-dation Trust, London, UK.




PAEDIATRICSOBSTETRICS I PEER REVIEWED


INTRODUCTION

Postpartum pyrexia is common and is usually due to bacterial infection of the breast, uri-

nary 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 38°C (100.4°F) 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 sep-

sis, 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 1846–1847 by the introduc-

tion of careful hand washing between attending each patient; this gradually became

widespread practice, but it was only when antibiotics became widely available in the

1940’s that the mortality from genital tract sepsis began to decline rapidly. In the trien-

nium 2006–2008, 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

Postpartum PyrexiaKevin G Glackin, MB, ChB, BAO, MRCOG, DFSRH; Margaret Ann Harper, OBE, MD, FRCOG, FRCPI, FFSRH







rise in the number of deaths from sepsis, particu-

larly sepsis due to group A streptococcal infection.

In 2006–2008, 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 ma-

ternal 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 accu-

rate figures are hard to find because of the variety

of definitions used and the difficulty of obtaining

data from the community as many postpartum in-

fections 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 2006–2008. The 2011 National Institute

for Health and Clinical Excellence (NICE) guideline

on caesarean section recommends routine antibi-

otic prophylaxis to reduce the incidence of infec-

tions 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 se-

vere maternal sepsis in the UK was initiated by the

UK Obstetric Surveillance System in June 2011.

AETIOLOGY

Postpartum pyrexia may have a wide variety of un-

derlying 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-

quences of persistent or relapsing maternal infec-

tion 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 episiot-

omy wounds, and cervical and vaginal lacerations

are all susceptible to bacterial infection. Organisms

may be acquired by contamination from an exter-

nal source or endogenously from the woman’s own

genital tract. Prolonged rupture of membranes, pro-

longed labour, operative vaginal delivery, caesarean

section, pre-existing vaginal infection or history of

group B streptococcal (GBS) infection, postpartum

haemorrhage, wound haematoma, retained pieces

Box 1. Definitions of postpartum pyrexia and puerperal sepsis.

• Although often used to describe any infection of the geni-tal 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 38°C (100.4°F) 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 38.5°C (101.3°F) 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).




of placenta, membranes or intrauterine clot, or re-

tained swabs all increase the risk of postpartum in-

fection. 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 de-

veloped world, is a risk factor for sepsis, as is mul-

tiparity.

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. Al-

though 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?

• 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?

• Have there been any problems with a perineal

or caesarean section wound?

• Was there excessive bleeding at the time of

delivery?

• Was there any difficulty with delivery of the

placenta or membranes?

• Has the lochia been unusually heavy, discol-

oured or smell offensive?

• 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?

Box 2. Postpartum pyrexia: causes related to pregnancy.

Genital tract causesEndometritisInfection of myometrium or parametriumPelvic abscessCaesarean wound infectionInfection of episiotomy or vaginal or cervical tearsNon-genital tract causesUrinary tract – cystitis or pyelonephritisBreast infection – mastitis or breast abscessRespiratory infection including pneumoniaVenous thromboembolismSeptic thrombophlebitisInfection of cannula sites including epidural cannulae

Box 3. Postpartum pyrexia: causes unrelated to pregnancy.

AppendicitisCholecystitisPancreatitisRespiratory tract infectionsCerebral abscessRheumatic endocarditisMyocarditisInfectious diseases, eg, malaria, tuberculosis, human immu-nodeficiency virus/AIDS

Malignant disease, eg, lymphomasParasitic infectionDrug feverOther




Postpartum pyrexia can be caused by pregnancy-related infections as well as coincidental causes unrelated to pregnancy.

Has the baby any evidence of infection?

• Are any other family members affected by sim-

ilar symptoms?

In hospital, the patient’s obstetric and mid-

wifery notes should be reviewed. In the commu-

nity, 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 communi-

cation between hospital and community carers is

emphasized in the maternal mortality report ‘Sav-

ing Mothers’ Lives 2003–2005’.

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 corticos-

teroids. Two days after admission, the fetal heart

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 antibiot-

ics. Within 24 hours, she deteriorated, developing

shortness of breath, tachycardia and continued py-

rexia. She was investigated for suspected pulmo-

nary embolus, which was excluded, but deteriorat-

ed 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 life-

threatening state can be very short. Prompt assess-

ment and treatment are essential. It is important to

check temperature, examine the lochia, and check

• Has the baby any evidence of infection?




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 as-

sociated 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 appro-

priate investigation.

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 con-

fusional states that may mislead the clinician, as

illustrated by one case in the triennial report ‘Why

Mothers Die 2000–2002’ of a woman with a per-

sistent tachycardia (130–170 beats per minute) and

increasingly bizarre behaviour after delivery, who

was mistakenly and tragically assumed to be hav-

ing panic attacks because she had a known history

of these. She was admitted to a psychiatric hospital

and, although rapidly transferred to the local gener-

al hospital, died soon afterwards. Autopsy revealed

an infected necrotic uterus.

Is It Necessary to Monitor Maternal Temperature

After Delivery?

In hospital, monitoring of maternal temperature

measurement during labour and after vaginal deliv-

ery or caesarean section is routine, but is not usu-

ally done after the woman returns home. The 2006

NICE guideline on postnatal care advises that rou-

tine 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 38.0°C, measurement

should be repeated within 4–6 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

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 pre-

sent, should be inspected for evidence of infection.

The breasts should be examined for any redness,

tenderness, localized masses, or cracked nip-

ples. 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

In postpartum

pyrexia, attention

should be paid to all

symptoms, not only

those related to the

genital tract




the deep veins or unilateral oedema of the lower

leg. If there are any other signs or symptoms

such as sore throat or lymphadenopathy, appro-

priate examination should be performed.

INVESTIGATIONS

The initial blood and microbiological investi-

gations 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 re-

peated 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 spe-

cialists 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, elec-

trocardiogram, 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. Rheu-

matic 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,

and women recently arrived from developing coun-

tries may have this condition. Two maternal deaths

occurred from infectious endocarditis in the triennium

2003–2005.

Case 2

A young woman in her second pregnancy had a spon-

taneous normal delivery in the midwifery-led unit and

went home after 8 hours. The community midwife vis-

ited her on day 3, when she was found to have py-

rexia of 39°C associated with rigors but no other symp-

toms. 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 breast-

feeding. A diagnosis of mastitis was made, and the

woman was commenced on oral antibiotics.

A full physical examination is indicated in the as-

sessment 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 en-

Box 4. Initial investigations for postpartum pyrexia.

Blood testsFull blood count (white cell count)C-reactive proteinBlood cultures (aerobic and anaerobic)Blood gases, lactate and coagulation screen if patient is clinically unwell

Urea and electrolytesLiver function testsSerum amylaseD-dimerMicrobiologyHigh and low vaginal swabsUrine microscopy and cultureThroat, wound, rectal swab or other swabs may be indicatedSputum culture if productive coughBreast milk if mastitis suspected




gorgement in the breast to be normal. Breast infec-

tions 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 10–14 days to ensure that in-

fection has been eradicated.

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 38°C or more, or is breathless, or has sus-

tained tachycardia, or has severe diarrhoea or vomit-

ing, or has chest, abdominal, uterine, renal angle or

other pain.

In hospital, immediate observations of tem-

perature, pulse, blood pressure, respiratory rate,

quality and amount of lochia, pain score, and level

of consciousness should be made, and then repeated

at regular intervals appropriate to the patient’s con-

dition. It is sometimes difficult to know whether a

patient is seriously ill. Routine use of a comprehen-

sive obstetric early warning scoring chart will show

changes in the patient’s condition and help the

earlier recognition of women who have or are de-

veloping 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 2003–2005 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

should be carried out as soon as possible. Treat-

ment with a combination of high-dose, broad-spec-

trum, 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 ad-

equate early intravenous antibiotic treatment may

be lifesaving. The onset of septicaemia in a pre-

viously healthy young woman is often insidious,

but as the disease advances her clinical condition

may deteriorate very rapidly and she may collapse

suddenly. If there is no response to the initial

antibiotic regimen within 24–48 hours or the pa-

tient’s condition worsens, the antibiotics should

be changed and gentamicin or similar antibiotic

added. It is very helpful to seek advice from a con-

sultant microbiologist.

Sepsis can have a

very rapid and

fulminating course,

and adequate early

intravenous antibiotic

treatment may be

lifesaving




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 patient’s condition.

• Patients with systemic infection can deteriorate very rapidly, so it is essential to commence high-dose, broad-spectrum, intra-venous 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.

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 immedi-

ately 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 con-

dition commenced as soon as possible. This may

include laparotomy and surgical drainage of ab-

scesses.

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 deliv-

ery, she developed pyrexia and shortness of breath.

Blood cultures were obtained, and she was com-

menced on broad-spectrum intravenous antibiotics.

She was admitted to the high dependency unit fol-

lowing further deterioration including respiratory

distress. Blood cultures were positive for group A

Streptococcus.

The triennial report of The Confidential En-

quiry into Maternal Death in the UK for 2006–2008

reports 13 deaths from beta-haemolytic Streptococ-

cus Lancefield group A (Streptococcus pyogenes).

This compares with eight deaths for 2003–2005

and three deaths in 2000–2002. This organism has

historically been associated with puerperal sepsis,

but maternal mortality was reduced following the

advent of antibiotics and antisepsis. This recent

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/tam-

pons, etc. Contamination is more likely when the

woman or close family, particularly children, have

sore throat and/or respiratory symptoms.

PREVENTION OF POSTPARTUM GENITAL TRACT INFECTION

Strict attention to hygiene, frequent hand wash-

ing, and aseptic precautions for all procedures per-

formed during labour and delivery are essential. Fre-

quent 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 ex-




amination. The 2003 Royal College of Obstetricians

and Gynaecologists (RCOG) Green-top Guideline

about group B streptococcal (GBS) disease recom-

mends that when there is a history of GBS infec-

tion, 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 sus-

pected, broad-spectrum antibiotic therapy including

an agent active against GBS should replace GBS-

specific antibiotic prophylaxis.

The placenta and membranes should always

be examined carefully after delivery to ensure that

they are complete. All swabs, needles and instru-

ments 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 recom-

mends that a single dose of a prophylactic broad-

spectrum antibiotic, such as ampicillin or a first-

generation cephalosporin, be offered to all women

having a caesarean section. The 2007 RCOG Green-

top Guideline about the management of a third- or

fourth-degree perineal tear recommends the use

of broad-spectrum antibiotics, including metroni-

dazole, to reduce the incidence of postoperative

infections and wound dehiscence. The 2011 RCOG

Green-top Guideline about operative vaginal de-

livery 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 re-

tained placenta after vaginal birth, a 2009 Cochrane

Database Review suggests following World Health

Organization advice of a single dose of metronida-

zole 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 treat-

ment. 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 speci-

alities, particularly microbiology, haematology, an-

aesthesia 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 moth-ers’ lives: reviewing maternal deaths to make motherhood safer: 2006–08. The Eighth Report on Confidential Enqui-ries into Maternal Deaths in the United Kingdom. BJOG 2011;118(suppl 1):1–203.

Maharaj D. Puerperal pyrexia: a review. Part I. Obstet Gynecol Surv 2007;62:393–399.

Maharaj D. Puerperal pyrexia: a review. Part II. Obstet Gynecol Surv 2007;62:400–406.

Palaniappan N, Menezes M, Willson P. Group A streptococcal puerperal sepsis: management and prevention. The Obstetri-cian & Gynaecologist 2012;14:9–16.

Sinha P, Otify M. Genital tract sepsis: early diagnosis, manage-ment and prevention. The Obstetrician & Gynaecologist 2012;14:106–114.

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):327–332.

About the AuthorsKevin 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.




Endometrial CarcinomaTH 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 annu-

ally, leading to 74,000 deaths.1 The stand-

ard treatment has been total abdominal

hysterectomy and bilateral salpingo-oo-

phorectomy (THBSO), and pelvic and aor-

tic lymphadenectomy, followed by adju-

vant 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 con-

troversies, summarizes the current posi-

tion, and highlights the possible treatment

strategies in the future.

PATHOLOGY

Two distinct types of EC have been defined

based on histology and molecular charac-

teristics of the tumour (Table 1). Type I tu-

mour or endometrioid carcinoma accounts

for 80–90% of all EC.2 It is related to un-

opposed oestrogen stimulation and is pre-

ceded by atypical hyperplasia. The typical

molecular alterations include PTEN gene

silencing and defects in DNA mismatch

repair genes.3 Patients with type I EC are

usually diagnosed at early stage and have

a 5-year survival rate of 74%.

Type II tumour includes clear cell,

papillary serous adenocarcinoma and car-

cinosarcoma. It is not oestrogen-related

and develops from atrophic endometrium.

In contrast to type I tumours, p53 gene

mutation, p16 gene inactivation and Her-

2/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 be-

tween 27% and 42%.3

RISK FACTORS

Chronic anovulation in premenopausal

women and peripheral conversion of an-

drostenedione 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 devel-

oping EC.4 A recent cohort study suggests

that increased EC risk is associated with

the use of combined oestrogen and pro-

Table 1. Comparison of FIGO 1988 with FIGO 2009 staging systems for endometrial carcinoma

FIGO 1988 FIGO 2009

Limited endometrium Stage IA Stage IA< ½ myoinvasion Stage IB Stage IA> ½ myoinvasion Stage IC Stage IBCervical glands involvement Stage IIA Not relevantCervical stromal involvement Stage IIB Stage IITumour invades the serosa and/or

adnexaeStage IIIA Stage IIIA

Positive peritoneal washing Stage IIIA Not relevantVaginal and/or parametrial involvement Stage IIIB Stage IIIBPelvic node metastasis Stage IIIC Stage IIIC1

Aortic node metastasis Stage IIIC Stage IIIC2Bladder and/or bowel mucosa

involvementStage IVA Stage IVA

Distant metastasis Stage IVB Stage IVB

JPOG-JanFeb-2013_CME_Final_HK_Endometrial Carcinoma.indd 37 1/23/13 11:08 AM


gestogen replacement for more than 10

years among women with body mass index

below 25 kg/m2.5

Lynch syndrome, or hereditary non-

polyposis colon cancer (HPNCC), is due to

germline mutation of one of the mismatch

repair genes, and it accounts for 2–3% 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

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

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 Papani-

colaou smear. The median age of EC pa-

tients is 61, and 20% of EC patients are

premenopausal.8

Dilatation and curettage (D&C) under

general anaesthesia used to be performed

for patients with abnormal uterine bleed-

ing,9 but outpatient procedures including

Vabra aspirator and Pipelle are preferred

nowadays. Although the Vabra aspirator

can sample a larger endometrial surface,10

a meta-analysis showed that Pipelle out-

performs the Vabra aspirator and offers a

sensitivity of 99.6% and 91% for diagnos-

ing EC in postmenopausal and premeno-

pausal women, respectively.11

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

The increased incidence of positive peri-

toneal 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-

raphy, as the negative predictive value is

99% and 100%, respectively.15,16 Whether

transvaginal ultrasonography, endometrial

biopsy, and hysteroscopy, alone or in com-

bination, is used to investigate abnormal

uterine bleeding depends on the availabil-

ity of expertise. Since none of the tests

is 100% sensitive, further investigation is

indicated if the symptom persists.

PREOPERATIVE INVESTIGATION

Many EC patients are old, obese and have

significant medical problems including

diabetes mellitus and hypertension. Thor-

ough health assessment and optimization

are essential before treatment to minimize

complications.

Contrast-enhanced magnetic reso-

nance imaging (MRI) is preferred to com-

puted tomography (CT) in assessing the

uterine and tumour size, myoinvasion,

cervical invasion, and nodal metastasis17

(Figure 1). The overall staging accuracy

rate is 85–93%. Positron emission tomog-

raphy/CT is the most sensitive method in

detecting nodal metastasis but does not

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.

a b c




provide accurate information on the pri-

mary tumour and is therefore not routinely

recommended.18

CA-125 may be checked before sur-

gery, and the level is raised in a third of

EC patients.19 Patients with abnormal CA-

125 are more likely to have higher tumour

grade and deep myoinvasion, nodal me-

tastasis, and poor survival.20

The International Federation of Gy-

necology and Obstetrics (FIGO) adopted a

surgical staging system for EC in 1988 to

replace the previously used clinical stag-

ing system that failed to categorize pa-

tients into different prognostic groups ac-

curately. The surgical staging system has

been revised in 2009, and the changes are

shown in Table 1.21

Based on the FIGO staging together

with histopathological risk factors such

as tumour grade, histological type and

lymph–vascular space invasion, EC pa-

tients can be roughly assigned to three

risk groups to guide the treatment22

(Table 2).

MANAGEMENT OF ENDOMETRIAL CARCINOMA

Surgical Treatment

Hysterectomy and Bilateral Salpingo-

oophorectomy

Surgery is the mainstay of treatment, and

THBSO is recommended not only to pa-

tients with early-stage disease but also

to the 10–25% patients diagnosed with

stage III or IV disease. Bilateral salpingo-

oophorectomy is recommended because of

the potential risk of tumour metastasis to

the ovary. Radical hysterectomy may be

offered to surgically fit EC patients with

cervical involvement, but clear survival

benefit from aggressive surgery is not

available.21 Preoperative irradiation has

not been shown to offer any benefit and

has largely been abandoned.

Staging Lymphadenectomy

Since only 10% of stage I EC patients have

pelvic nodal metastasis and about 50% of

the nodal metastasis are noticeable in-

traoperatively,22 routine pelvic and para-

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 aor-

tic 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 be-

low 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

appears to more appropriate. However,

the current technology is imprecise in de-

termining these two tumour characteris-

tics 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 pathologi-

cal assessment may provide the answer,

but such a service is not readily available.

Therapeutic Lymphadenectomy

Retrospective studies suggest that mul-

tiple-site lymphadenectomy, removal of

a larger number of lymph nodes, and de-

bulking of enlarged metastatic nodes offer

survival benefits.24–26 However, the thera-

peutic benefit of pelvic lymphadenectomy

was not supported by two recently pub-

lished 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 no-

lymphadenectomy group were diagnosed

to have nodal metastasis (13.3% vs 3.2%)

Table 2. Endometrial carcinoma classified into three different risk groups

Grade I Grade II Grade III

Stage IA Low Low Intermediate (without LVSI)

Stage IB Intermediate Intermediate HighStage II and above High High High

LVSI = lymph–vascular space invasion.



and developed postoperative complica-

tions. However, the 5-year disease-free

survival and overall survival (OS) were

similar between the two groups.26

A Study in the Treatment of Endo-

metrial Cancer (ASTEC) trial randomized

patients to THBSO with or without lym-

phadenectomy. Patients diagnosed to

have intermediate-/high-risk early-stage

disease were subjected to a second ran-

domization to pelvic radiotherapy or no

radiotherapy postoperatively. The progres-

sion-free survival (PFS) and OS were not

different between the two groups.27

Surgical Approaches

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, bi-

lateral salpingo-oophorectomy, and pelvic

and aortic node dissection. Laparoscopic

approach was associated with longer op-

erative time, less postoperative morbidi-

ties, and shorter hospital stay. There was

no difference in the intraoperative com-

plication 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 in-

creased with the body mass index and age.

It appears that laparoscopic surgery was

applicable to EC patients when trained

surgeons were available.28 A meta-analysis

showed no difference in the OS, disease-

free survival and cancer-related death be-

tween the laparoscopic and open surgery.29

Robot-assisted technique is an ad-

vanced mode of minimally invasive sur-

gery, and the major advantages of robot-

assisted surgery are a steep learning curve

and no association between an increase in

body mass index and a higher conversion

rate.30,31

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. How-

ever, there has never been any evidence to

support that pelvic RT improves the surviv-

al. Recently published studies have further

questioned the role of adjuvant pelvic RT

in intermediate-risk EC patients.

The Post Operative Radiation Ther-

apy in Endometrial Carcinoma (PORTEC)

study randomized intermediate-risk EC pa-

tients to adjuvant pelvic RT and no further

treatment after THBSO.32 After a median

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 con-

trol group (79% vs 21%), the actuarial

5-year OS rates (81% vs 85%) and the EC-

related death rates (9% vs 6%) were not

significantly different between the two

groups.

The GOG 99 study randomized inter-

mediate-risk node-negative EC patients

to external beam RT or observation.33 The

24-month cumulative recurrence rate was

3% in the RT group and 12% in the con-

trol group, and the difference was mostly

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 dem-

onstrated.

A Study in the Treatment of Endome-

trial Cancer (ASTEC) and EN.5 trials were

two distinct studies, and their data were

pooled in a planned analysis. Primary sur-

gery did not always include lymphadenec-

tomy, and the patients were randomized

to postoperative external beam RT or ob-

servation. 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 sur-

vival benefit by giving external RT, but the

treatment-related morbidity would be sig-

nificantly higher.32–34

Since vaginal vault recurrence is

the most common site of recurrence, the

PORTEC-2 study randomized high-inter-

mediate-risk patients to external beam RT

or vaginal brachytherapy (VBT). The esti-

mated rates of vaginal recurrence were

1.8% for VBT and 1.6% for external beam

RT. There were no differences in the over-

all 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 rec-

ommended for high-intermediate-risk EC

patients and routine pelvic RT is not.35

Chemotherapy

Chemotherapeutic Regime

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 taxa-

nes, anthracyclines, ifosfamide and plati-

num drugs are the most effective agents

for EC, and a response rates of 20% can

be expected.36–38

One RCT showed higher response

rate and longer PFS with combined doxo-

rubicin and cisplatin than with doxoru-

bicin alone.39 The GOG 177 study further

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 doxorubicin–cisplatin.40 TAP has

therefore become the standard treatment

in patients with advanced stage or recur-

rent 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 40–63% response rate when used in

chemotherapy-naive EC patients.41 The

GOG 209 study is a RCT comparing the per-

formance 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 administra-

tion, and manageable toxicity. A number

of clinical trials have commenced to deter-

mine the role of this combination.

Radiotherapy Versus Chemotherapy

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

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. How-

ever, 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 postop-

erative adjuvant chemotherapy consisting

of eight cycles of doxorubicin and cisplatin

with whole abdominal irradiation in stage

III and IV EC patients with residual dis-

ease < 2 cm, and showed that the PFS and

OS were better after chemotherapy than

whole abdominal irradiation.44

It therefore appears that patients

with high-risk features are more likely to

benefit from chemotherapy whilst ade-

quately surgically staged low-risk patients

with low metastatic risk do not.

Radiotherapy Followed By

Chemotherapy

Since chemotherapy appears more effec-

tive in reducing distant metastasis whilst

radiotherapy is more effective in reduc-

ing pelvic recurrence, a sequential use of

chemotherapy after RT appears advanta-

geous.42

The joint study by Nordic Society of

Gynaecological Oncology/European Or-

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 im-

proved PFS and cancer-specific survival if

chemotherapy was given after the comple-

tion 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 sequen-

tially after RT, further studies are needed

to define which patient groups should

receive chemotherapy and which chemo-

therapy 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-depend-

ent tumour, and progesterone has been

used in EC patients after surgery. No partic-

ular progestational agent has been shown

to be superior to the rest, and the duration

of usage varies from months to an indefi-

nite 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 re-



current EC showed no evidence of survival

improvement.48 When progestogen is used

for palliation in EC patients with advanced

disease or recurrence, a 11–56% response

rate and PFS time of 2.5 to 14 months

might be achieved.49 Tamoxifen and aro-

matase inhibitors have been used in EC,

but the response rates were modest.

Fertility-sparing Therapy

About 3–5% of EC patients are below the

age of 40, and some of them may have

strong desire to preserve fertility.50,51 It

cannot be overemphasized that fertility-

sparing treatment using high-dose pro-

gestogen 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 applica-

ble.52

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

(26%).53 Preoperative MRI is performed to

assess myoinvasion although the nega-

tive predictive value of MRI in predicting

absence of myoinvasion is only 42–49%.17

Daily 100–400 mg megestrol acetate

or 200–600 mg medroxyprogesterone ac-

etate are most commonly used. Higher re-

sponse rate was not observed in patients

with advanced or recurrent EC treated

with 1,000 mg medroxyprogesterone ac-

etate 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 dura-

tion often extends beyond 6 months if a

response is observed.

D&C at 3-monthly interval is manda-

tory after fertility-sparing treatment be-

cause 30% of patients would recur even

after complete response. About 30–50%

of responders achieve pregnancy, with

or without assistance from reproductive

technology.56 Hysterectomy is advisable

after completing the family.

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 4–14% partial response rate

in heavily pretreated and chemotherapy-

naive EC patients.57 Bevacizumab dem-

onstrated 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

Key points

• Endometrial carcinoma (EC) is a heterogeneous disease with differ-ent 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 bene-

fit.• 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 uncon-

trolled 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.




targeted therapy are important to maxi-

mize the benefits of targeted therapy.

POSTOPERATIVE SURVEILLANCE

About 15% of EC recur, and the common-

est site of recurrence is at the vaginal

vault.58 Most of the recurrences develop

within the first 2 years and 75% within 3

years after treatment.

The National Comprehensive Cancer

Network guidelines recommend visits eve-

ry 3 to 6 months for 2 years then 6 months

or annually.59 More intense follow-up may

be indicated if the patient has high risk

factor for recurrence or develops morbidi-

ties 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 ex-

amination of the genital tract is a must.

The cost-effectiveness of routine vaginal

cytology in asymptomatic women has been

questioned.60 CA-125 may be used if the

marker is raised before treatment. Imag-

ing studies at interval for asymptomatic

patients is not routinely recommended.

MANAGEMENT OF RECURRENCES

A meta-analysis has shown that complete

surgical cytoreduction in patients with

advanced-stage or recurrent EC was asso-

ciated with improved survival.59 Treatment

of patients with recurrences has to be in-

dividualized according to the tumour size,

tumour grade, site of recurrence, and prior

or no prior irradiation.

For patients with vaginal vault recur-

rence 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 re-

lapse was 73%.32

For nodal recurrences that occur at

the pelvic sidewall or aortic areas, RT is

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. Hor-

monal therapy might be used for asymp-

tomatic patients with receptor-positive

grade 1 disease, and chemotherapy is

used for symptomatic or receptor-negative

patients. Currently, there is no Food and

Drug Administration–approved agent for

second-line salvage therapy.

About the AuthorDr 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.

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;127:2893–2917.2. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 1983;15:10–17. 3. Gadducci A, Greco C. The evolving role of ad-juvant therapy in endometrial cancer. Crit Rev Oncol Hematol 2011;78:79–91.4. Bergman L, Beelen ML, Gallee MP, Hollema H, Benraadt J, van Leeuwen FE; Comprehensive Cancer Centres’ ALERT Group. Risk and progno-sis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000;356:881–887.5. Razavi P, Pike MC, Horn-Ross PL, Temple-man C, Bernstein L, Ursin G. Long-term post-menopausal hormone therapy and endome-trial cancer. Cancer Epidemiol Biomarkers Prev 2010;19;475–483.6. Backes FJ, Cohn DE. Lynch syndrome. Clin

Obstet Gynecol 2011;54:199–214.7. Bjørge T, Stocks T, Lukanova A, et al. Meta-bolic syndrome and endometrial carcinoma. Am J Epidemiol 2010;171:892–902.8. Creasman WT, Odicino F, Maisonneuve P, et al. Carcinoma of the corpus uteri. J Epidemiol Biostat 2001;6:47–86.9. 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;283:261–266.10. Rodriguez GC, Yaqub N, King ME. A com-parison of the Pipelle device and the Vabra as-pirator 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;168:55–59.11. Dijkhuizen FP, Mol BW, Brolmann HA, Heintz AP. The accuracy of endometrial sampling in the

diagnosis of patients with endometrial carci-noma and hyperplasia: a meta-analysis. Cancer 2000;89:1765–1772.12. Clark TJ, Voit D, Gupta JK, Hyde C, Song F, Khan KS. Accuracy of hysteroscopy in the diagnosis of endometrial cancer and hyperpla-sia: a systematic quantitative review. JAMA 2002;288:1610–1621.13. Polyzos NP, Mauri D, Tsioras S, Messini CI, Valachis A, Messinis IE. Intraperitoneal dissem-ination of endometrial cancer cells after hyster-oscopy: a systematic review and meta-analysis. Int J Gynecol Cancer 2010;20:261–267.14. Chang YN, Zhang Y, Wang YJ, Wang LP, Duan H. Effect of hysteroscopy on the perito-neal dissemination of endometrial cancer cells: a meta-analysis. Fertil Steril 2011;96:957–961.15. Langer RD, Pierce JJ, O’Hanlan KA, et al. Transvaginal ultrasonography compared with endometrial biopsy for the detection of endo-metrial disease. Postmenopausal Estrogen/

Progestin Interventions Trial. N Engl J Med 1997;337:1792–1978.16. Gull B, Carlsson SA, Karlsson B, Ylöstalo P, Milsom I, Granberg S. Transvaginal ultrasonog-raphy of the endometrium in women with post-menopausal bleeding: is it always necessary to perform an endometrial biopsy? Am J Obstet Gynecol 2000;182:509–515.17. Lee JH, Dubinsky T, Andreotti RF, et al. ACR appropriateness Criteria® pretreatment evalua-tion and follow-up of endometrial cancer of the uterus. Ultrasound Q 2011;27:139–145.18. 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 institute dedicated to CME learning. Read the article ‘Endometrial Carcinoma’ and answer the following questions. This JPOG article has been accredited for CME by the Hong Kong College of Obstetricians and Gynaecologists.

CME Answers for JPOG Nov/Dec 2012

HKCOG CME Article: Postmenopausal Bleeding

Answers

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Date: Please mail your completed answer sheet back to:The SecretariatHong Kong College of Obstetricians & GynaecologistsRoom 805, Hong Kong Academy of Medicine Jockey Club Building99 Wong Chuk Hang Road, Aberdeen, Hong Kong

CME Article


Answer True or False to the questions below.

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.

True False

CME Article


Answer True or False to the questions below.

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.

True False

This continuing medical education service is brought to you by the Medical Progress Institute, an institute dedicated to CME learning. Read the article ‘Endometrial Carcinoma’ and answer the following questions.Answers are shown at the bottom of this page. We hope you enjoy learning with JPOG.


JPOG February 2013 HK

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