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JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY
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GYNAECOLOGY
Endometriosis
OBSTETRICS
Hyperemesis, Gastrointestinal & Liver Disorders in Pregnancy

PAEDIATRICS
The Limping Child: An Approach to Diagnosis & Management

CME ARTICLE
HKCOG Guidelines Prediction of High-risk Pregnancies

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MAY / JUN 2012 Vol. 38 No. 3
Journal Watch
89 Herpes simplex vaccine Pertuzumab and trastuzumab in breast cancer Harms from breast cancer screening 90 Overdiagnosis from screening mammography Frequency of bone density testing in older women Neoadjuvant chemotherapy plus bevacizumab for breast cancer
89
91 Hydatidiform mole, hCG concentrations, and chemotherapy Effectiveness of trained traditional birth attendants 92 Home vs hospital birth in England Extended nevirapine for breastfeeding infants of HIV-infected mothers
91
Editorial Board
Board Director, Paediatrics Professor Pik-To Cheung Associate Professor Department of Paediatrics and Adolescent Medicine The University of Hong Kong Board Director, Obstetrics and Gynaecology Professor Pak-Chung Ho Head, Department of Obstetrics and Gynaecology The University of Hong Kong
Professor Biran Affandi University of Indonesia Dr Karen Kar-Loen Chan The University of Hong Kong Associate Professor Oh Moh Chay KK Womens and Childrens Hospital, Singapore Associate Professor Anette Jacobsen KK Womens and Childrens Hospital, Singapore Professor Rahman Jamal Universiti Kebangsaan Malaysia Dato Dr Ravindran Jegasothy Hospital Kuala Lumpur, Malaysia Associate Professor Kenneth Kwek KK Womens and Childrens Hospital, Singapore Dr Siu-Keung Lam Kwong Wah Hospital, Hong Kong Professor Terence Lao Chinese University of Hong Kong Dr Kwok-Yin Leung The University of Hong Kong
Dr Tak-Yeung Leung Chinese University of Hong Kong Professor Tzou-Yien Lin Chang Gung University, Taiwan Professor Somsak Lolekha Ramathibodi Hospital, Thailand Professor Lucy Chai-See Lum University of Malaya, Malaysia Professor SC Ng National University of Singapore Professor Hextan Yuen-Sheung Ngan The University of Hong Kong Professor Carmencita D Padilla University of the Philippines Manila Professor Seng-Hock Quak National University of Singapore Dr Tatang Kustiman Samsi University of Tarumanagara, Indonesia Professor Perla D Santos Ocampo University of the Philippines Associate Professor Alex Sia KK Womens and Childrens Hospital, Singapore
Dr Raman Subramaniam Fetal Medicine and Gynaecology Centre, Malaysia Professor Walfrido W Sumpaico MCU-DFT Medical Foundation, Philippines Professor Cheng Lim Tan KK Womens and Childrens Hospital, Singapore Associate Professor Kok Hian Tan KK Womens and Childrens Hospital, Singapore Dr Surasak Taneepanichskul Chulalongkorn University, Thailand Professor Eng-Hseon Tay Thomson Womens Cancer Centre, Singapore Professor PC Wong National University of Singapore Dr George SH Yeo KK Womens and Childrens Hospital, Singapore Professor Hui-Kim Yap National University of Singapore Professor Tsu-Fuh Yeh China Medical University, Taiwan
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MAY / JUN 2012 Vol. 38 No. 3
Review Articles
Gynaecology
93 Endometriosis Endometriosis is a very complex gynaecological condition characterized by the presence of ectopic
endometrial tissue outside the uterine cavity and is frequently associated with debilitating pelvic pain and infertility. The management of endometriosis can be challenging and should be tailored to each individuals circumstances. Francesca Raffi, Saad Amer
93
Review Articles
Obstetrics
105 Hyperemesis, Gastrointestinal and Liver Disorders in Pregnancy This review aims to discuss some of the common and serious conditions of the gastro-intestinal,
hepatic and biliary tracts in pregnancy. Clare Cuckson, Sarah Germain
105
Ben Yeo
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Review Articles
Paediatrics
117 The Limping Child: An Approach to Diagnosis and Management Investigating a child with a limp requires careful consideration because the differential diagnoses
are broad. The condition is rarely an emergency, but it can be serious and debilitating. Angela Cox, Roger Allen
Continuing Medical Education
117
125 HKCOG GuidelinesPrediction of High-risk Pregnancies

This guideline by The Hong Kong College of Obstetricians and Gynaecologists (HKCOG) examines the scientific evidence about capacities to predict high-risk obstetric problems. The Hong Kong College of Obstetricians and Gynaecologists
125
The Journal of Paediatrics, Obstetrics and Gynaecology contains articles under licence from UBM Media LLC. The articles appearing on pages 4953, and pages 6780 are reprinted with permission of Consultant for Pediatricians. Copyright 2011 UBM Media LLC. All rights reserved.
Review Articles
Comprehensive reviews providing the latest clinical information on all aspects of the management of medical conditions affecting children and women.
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Interesting cases seen in general practice and their management.
Hyperemesis, Gastrointestinal & Liver Disorders in Pregnancy 2012 UBM Medica
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Journal Watch
Harms from breast cancer screening
HSV-1 genital disease. Against HSV-1, infection
GYNAECOLOGY
Herpes simplex vaccine
with or without disease, efficacy was 35%. There was no efficacy (-8%) against HSV-2 infection. The HSV-2 vaccine was effective against HSV-1 genital disease but not against HSV-2 infection; the reasons are unexplained. An HSV vaccine suitable for general use is not yet available.
Belshe RB et al. Efficacy results of a trial of a herpes simplex vaccine. NEJM 2012; 366: 3443.
Pertuzumab and trastuzumab in breast cancer

About 20% of breast cancers are human epidermal growth factor receptor 2 (HER2) positive. Treatment with the humanized monoclonal anti-HER2 antibody, trastuzumab, improves outcomes. A new anti-HER2 antibody, pertuzumab, binds to a different part of HER2 and could add to the effectiveness Herpes simplex viruses 1 (HSV-1) and 2 (HSV-2) both cause genital infections, and HSV-1 infections are increasingly prevalent. Transmission from mother to newborn infant may cause severe disease. Trials of an HSV-2 glycoprotein D-based subunit vaccine have shown around 75% efficacy against HSV-2 disease among women seronegative for both HSV-1 and HSV-2 antibodies. Now, a trial in the USA and Canada has surprisingly shown efficacy against HSV-1 genital disease but not HSV-2 disease. The trial included 8,323 women aged 1830 years who were doubly seronegative (HSV-1 and HSV-2). Randomization was to the HSV-2 glycoprotein D vaccine with alum and 3-0-deacylated monophosphoryl lipid A as an adjuvant or hepatitis A vaccine, at months 0, 1, and 6. The HSV-2 vaccine induced ELISA and neutralizing antibodies to HSV2. The vaccine efficacy was only 20% against any genital herpes simplex infection but 58% against
Baselga J et al. Pertuzumab plus trastuzumab and docetaxel for metastatic breast cancer. NEJM 2012; 366: 109119; Gradishar WJ. HER2 therapy an abundance of riches. Ibid: 176178 (editorial).
The Forrest Report of the 1980s led to the introduction of UKs breast screening programme. Later, a Cochrane review showed that for every 2,000 women invited for screening over a 10-year period, only one would have her life prolonged and ten falsepositive women would be treated unnecessarily. More than 200 women would suffer significant psychological distress because of false-positive results. Now, a new analysis has updated the Forrest Report by presenting data in terms of qualityadjusted life-years (QALYs). Using data from trial meta-analyses and 1985 English data for breast cancer mortality and surgery, two cohorts of 100,000 women aged 50 were followed by computer modelling. One cohort was invited for mammographic screening and the other was not. Mortality was reduced, and surgery increased in the screening group according to available data. The cumulative net QALYs gained from screening were explored in five scenarios. Adding harms in one of these scenarios halved the gains in QALYs. Subsequent scenarios showed negative
of trastuzumab. Now, a phase III trial has demonstrated this increased effectiveness. At 204 centres in 25 countries, a total of 808 women with metastatic HER2-positive breast cancer were randomized to treatment with trastuzumab and docetaxel with or without pertuzumab. Progression-free survival was 18.5 months (pertuzumab) vs 12.4 months (controls), a significant 38% advantage with pertuzumab. At an interim analysis of overall survival, there had been 69 deaths in the pertuzumab group and 96 in the control group, an insufficient difference to stop the trial at that point. Toxicity was similar in the two groups. The addition of pertuzumab to trastuzumab and docetaxel improved progression-free survival.
JPOG MAY/JUN 2012 89
QALYs during the first 7 years after screening. Among women aged 6070, a greater reduction in mortality led to a higher gain in QALYs only in the longer term. Varying the data in the model altered the QALY results, but a pattern of low or negative net QALYs in the early years after starting screening remained. According to this computer model, screening has a negative effect on quality of life in the early years, followed by a net gain in QALYs but at a slower rate than had been expected.
Raftery J, Chorozoglou M. Possible net harms of breast cancer screening: updated modelling of Forrest Report. BMJ 2012; 344 (Jan 14): 14 (343: d 7627); Hackshaw A. Benefits and harms of mammography screening. Ibid: 344:7 (d8279) (editorial).
estimation of rates of overdiagnosis among women aged 5069 in Isre, France, between 1991 and 2006. Overdiagnosis accounted for 1.5% of cases of invasive cancer and 28% of cases of carcinoma in situ diagnosed either clinically or at screening mammography. With analysis restricted to screening mammography cases, the estimated overdiagnosis rates were 3.3% and 31.9%, respectively. The estimated overdiagnosis rates in this study were smaller than expected.
Seigneurin A et al. Overdiagnosis from non-progressive cancer detected by screening mammography: stochastic simulation study with calibration to population based registry data. BMJ 2012; 344 (Jan 14): 15 (d7017); Hackshaw A. Benefits and harms of mammography screening. Ibid: 7 (d8279).
These investigators conclude that osteoporosis would develop in < 10% of older postmenopausal women with rescreening intervals of about 15 years for those with an initially normal BMD or mild osteopenia, 5 years for those with moderate osteopenia, and 1 year for those with advanced osteopenia.
Gowlay ML et al. Bone-density testing interval and transition to osteoporosis in older women. NEJM 2012; 366: 225233.
Neoadjuvant chemotherapy plus bevacizumab for breast cancer

In three studies, bevacizumab, a monoclonal an-
Overdiagnosis from screening mammography
Frequency of bone density testing in older women

US guidelines recommend bone density screening for women aged 65 years or older, but the optimum frequency of screening is uncertain. A US longitudinal cohort study has provided more guidance. The study included 4.957 women (99% white) aged 67 or older at four sites in the USA. They had bone mineral density (BMD) assessment with dual-energy X-ray absorptiometry scanning at baseline and at follow-up over a period of 15 years. None had a history of hip or clinical vertebral fracture or treatment for osteoporosis, and none had osteoporosis on the baseline BMD screening. The estimated BMD testing interval (time to the development of osteoporosis before hip or clinical vertebral fracture in 10% of women) was 16.8 years with a normal baseline BMD, 17.3 years with mild osteo-
tibody against vascular endothelial growth factor A, has been shown to improve outcomes when added to chemotherapy for the treatment of human epidermal growth factor receptor (HER)2-negative metastatic breast cancer. Now, two successive reports in the New England Journal of Medicine have shown that adding bevacizumab to neoadjuvant chemotherapy significantly increased the rate of complete pathological response in early HER2negative breast cancer. A total of 1,948 patients with early HER2negative breast cancer were randomized to treatment with neoadjuvant chemotherapy (epirubicin and cyclophosphamide followed by docetaxel) with or without bevacizumab. Complete pathological response (absence of invasive and intraductal disease in the breast and the axillary lymph nodes) occurred in 18.4% with bevacizumab and 14.9% without bevacizumab, a significant 29% improvement with bevacizumab. Breast-conserving surgery was possible in 66.6% of patients in each of the two groups. Grade 3 or 4 toxic effects (febrile neutropenia, mucositis, the handfoot syndrome, infection, or hypertension) were more frequent with bevacizumab. The addition of bevacizumab signifi-
Although screening mammography results in reduced mortality from breast cancer among women aged 5070, there are disadvantages, including anxiety from false-positive results, low-dose radiation, and overdiagnosis. Workers in France have reported a stochastic simulation model study with
penia, 4.7 years with moderate osteopenia, and 1.1 years with advanced osteopenia (normal = T score at femoral neck and total hip of -1.00 or higher; mild osteopenia = t score -1.01 to -1.49; moderate osteopenia = T score -1.50 to -1.99; advanced osteopenia = T score -2.00 to -2.49).
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cantly increased the rate of complete pathological response, most significantly in patients with triplenegative tumours. In North America, a total of 1,206 patients with early HER2-negative breast cancer were randomized to neoadjuvant therapy with docetaxel alone or with either gemcitabine or capecitabine for four cycles followed by doxorubicincyclophosphamide for four cycles. At the same time, they were also randomized to bevacizumab or no bevacizumab. The addition of either gemcitabine or capecitabine to docetaxel did not significantly improve rates of complete pathological response, and both gemcitabine and capecitabine were associated with increased toxicity. Adding bevacizumab increased the rate of complete pathological response from 28.2% to 34.5%, a significant effect. Bevacizumab was associated with increased rates of hypertension, left ventricular systolic dysfunction, the handfoot syndrome, and mucositis. Adding bevacizumab to neoadjuvant chemotherapy increased the rate of complete pathological response in both these studies.
Von Minckwitz G et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. NEJM 2012; 366: 299309; Bear HD et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. Ibid: 310320; Montero AJ, Vogel C. Fighting fire with fire: rekindling the bevacizumab debate. Ibid: 374375 (editorial).
this suggestion. The study included 13,960 women with a diagnosis of hydatidiform mole between January 1993 and May 2008. Among these women, 76 (< 1%) had persistently high (> 5 IU/L) hCG levels at 6 months. Sixty-six of these patients continued under surveillance, and hCG levels returned to normal without chemotherapy in 65 (98%). The one patient whose hCG levels remained high had chronic renal failure as a cause of the high levels and remained otherwise well. Ten patients received chemotherapy, and hCG levels returned to normal in eight of them (80%). The remaining two patients had persistent, slightly high (611 IU/L) levels, but there were no associated clinical problems off treatment. There were no deaths, and outcomes were similar with or without chemotherapy. These researchers conclude that a policy of continued surveillance without chemotherapy seems acceptable for patients with raised (not younger (< 16 years) and older (> 45 years) women. Molar pregnancies present with vaginal bleeding in the first trimester, and levels of human chorionic gonadotropin (hCG) in serum and urine are raised. Following dilatation and curettage, hCG levels return to normal in about 92% of cases. Malignant transformation occurs in about 15% of cases after complete hydatidiform mole and 0.51% after partial hydatidiform mole. Chemotherapy, usually with methotrexate or dactinomycin, is then necessary. All women with a hydatidiform mole in the UK very high) but falling hCG levels at 6 months after evacuation of a hydatidiform mole.
Agarwal R et al. Chemotherapy and human chorionic gonadotropin concentrations 6 months after uterine evacuation of molar pregnancy: a retrospective cohort study. Lancet 2012; 379: 130135; Cheung ANY, Chan KKL. Perplexing hCG profile after evacuation of hydatidiform mole. Ibid: 98100 (comment).
Effectiveness of trained traditional birth attendants

Traditional birth attendants are in charge at many births in developing countries, and giving them extra training and resources can improve obstetric and neonatal outcomes. A meta-analysis of six randomized controlled trials and seven non-randomized studies has confirmed that training these workers results in improved results. A total of 138,549 patients were included in the randomized trials that assessed the effects of training and support for traditional birth attendants.
OBSTETRICS
are referred for hCG monitoring and surveillance to one of three national centres in Dundee, Sheffield, and London. Post-mole gestational trophoblastic
Hydatidiform mole, hCG concentrations, and chemotherapy

In the UK, hydatidiform moles constitute between 1 and 3 of every 1,000 pregnancies, but they are more common in east Asia. They are more common in
neoplasia is suspected when hCG levels plateau or increase or remain raised at 6 months although they are falling. Evidence suggests, however, that an increased but falling hCG level at 6 months after uterine evacuation may not necessarily necessitate chemotherapy. A retrospective study at a single hospital in London, England. has added support to
Meta-analysis showed significant reductions of 24% in perinatal mortality and 21% in neonatal mortality after such training and support. The nonrandomized trials included 72,225 patients. Metaanalysis showed significant reductions of 30% in perinatal mortality and 39% in neonatal mortality. Meta-analysis of six studies of maternal mortality showed a non-significant reduction of 20% after training and support of traditional birth attendants. Training and support of traditional birth attendants in developing countries improves outcomes according to the type and extent of training and support provided. Perinatal, neonatal, and maternal mortalities may all be improved.
Wilson A et al. Effectiveness of strategies incorporating training and support of traditional birth attendants on perinatal and maternal mortality: meta-analysis. BMJ 2012; 344 (Jan 21): 16 (2011; 343: d7102); Hodnett E. Traditional birth attendants are an effective resource. Ibid: 9 (e365) (editorial).
come events was greater for planned home deliveries (9.3 per 1,000) than for deliveries planned on an obstetric unit (5.3 per 1,000) or on a midwifery unit (4.5 per 1,000). Transfers from home or midwifery unit to an obstetric unit were necessary, more often for nulliparous women. Operative and instrumental deliveries were more frequent for deliveries planned to be in an obstetric unit. For low-risk pregnancies in multiparous women, home birth or birth in an obstetric unit is generally safe and there is a lower risk of obstetric intervention. Among nulliparous women, there is a higher risk of poor outcomes with home birth.
Birthplace in England Collaborative Group. Perinatal and maternal outcomes by planned place of birth for healthy women with low risk pregnancies: the Birthplace in England national prospective cohort study. BMJ 2012; 344 (Jan 21): 17 (2011; 343: d7400).
ceived oral nevirapine suspension for the first 6
Home vs hospital birth in England

A national prospective cohort study in England has confirmed the safety of planned home birth for lowrisk women. The study included 64,538 women with low-risk pregnancies with delivery between April 2008 and April 2010. The primary outcome was a composite of perinatal death, and intrapartum morbidity (stillbirth during labour, early neonatal death, neonatal encephalopathy, meconium aspiration syndrome, brachial plexus injury, or fractures of humerus or clavicle). Overall, the incidence of the primary outcome was similar for births planned at home (4.2 primary outcome events per 1,000 births), in an obstetric unit (4.4 per 1,000), and in a midwifery unit (3.5 per 1,000). On subgroup analysis, planned place of birth had no significant effect on outcomes among multiparous women. Among nulliparous women, the incidence of primary out-
PAEDIATRICS
weeks. Those who were HIV-negative at 6 weeks were then randomized to continued nevirapine, or placebo, until the age of 6 months or until stop-
Extended nevirapine for breastfeeding infants of HIVinfected mothers

Although breastfeeding is essential in sub-Saharan Africa for the infants nutrition and protection from infection, prolonged breastfeeding may lead to mother-to-child transmission of human immunodeficiency virus (HIV) 1. Antiretroviral therapy is given to protect against antenatal and intrapartum HIV transmission, but prolonged prophylaxis during breastfeeding has been difficult to achieve in many countries. Now, successful prophylaxis during breastfeeding has been reported from South Africa, Tanzania, Uganda, and Zimbabwe. The study included 1,527 breastfeeding infants of HIV-1-positive mothers. The infants re-
ping breastfeeding. Between the ages of 6 weeks and 6 months, HIV-1 infection was acquired by 1.1% in the extended nevirapine group and 2.4% in the placebo group, a significant 54% improvement with extended nevirapine. At 6 months of age, mortality, combined mortality and HIV-1 infection, and severe adverse event rates were similar in the two groups. Extended nevirapine prophylaxis given to the breastfeeding infant is effective for at least 6 months. It should be used along with other provisions such as routine HIV screening in pregnancy, and antiretroviral interventions during pregnancy, labour, and delivery.
Coovadia HM et al. Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 379: 221228.
GYNAECOLOGY
Peer Reviewed
Endometriosis
Francesca Raffi, MBChB, MRCOG; Saad Amer, MBChB, MSc, MRCOG, MD
INTRODUCTION
Endometriosis is a common gynaecological condition affecting about 610% of women of reproductive age and can be a debilitating disease. It is the second most common reason for surgery in premenopausal patients. It is defined as the presence of endometrial-like tissue outside the uterine cavity, leading to a chronic inflammatory reaction. The exact aetiology is unknown, but the retrograde menstruation model is the most widely accepted theory explaining the development of pelvic endometriosis. According to this model, menstrual blood containing endometrial fragments passes through the fallopian tubes into the pelvic cavity, resulting in the formation of peritoneal endometrial deposits. There are three distinctive pathological types of pelvic endometriosis: superficial peritoneal implants, ovarian endometriomas, and deep infiltrating nodular lesions. The extent of the disease is very variable and often does not correlate with the severity of symptoms. Although it can sometimes be asymptomatic (in about 20% of cases), endometriosis is frequently associated with severe pain and infertility. Several management options exist for endometriosis and the choice depends on several factors such as age, fertility, severity of the symptoms, and extent of the disease. This review presents three different cases of endometriosis with different complexities and presentations. The diagnosis and various medical and surgical treatment options available to the clinician will be discussed.
Pathological Types of Endometriosis

Superficial peritoneal endometriosis: peritoneal implants consist of glandular and stromal tissue and respond to the hormonal changes associated with the menstrual
GYNAECOLO GY G YNAECOLOGY
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cycle showing cyclical changes similar but not identical to the normal endometrium. These implants heal by fibrosis. Deep infiltrating (adenomatous) endometriosis: this type of endometriosis is characterized by proliferative fibromuscular tissue with sparse endometrial glandular and stromal tissue (similar to adenomyosis), with no surface epithelium. Unlike the peritoneal endometriosis, deep endometriosis does not show significant changes during the menstrual cycle. These nodules are typically present in the recto-vaginal space and can involve the uterosacral ligament, the posterior vaginal wall, and the anterior rectal wall. They can also extend laterally and affect the ureters. Ovarian endometriomas: an endometrioma is an ovarian cyst lined by endometriotic tissue and containing dark brown or chocolate-coloured fluid, which results from recurrent chronic bleeding from the endometriotic implants. In long-standing endometriomas, the endometriotic tissue is gradually replaced by fibrotic tissue.
CASE 1
A 17-year-old patient presented to her general practitioner with a 6-month history of severe and excruciating dysmenorrhoea. Pelvic examination revealed no abnormality, and a diagnosis of primary physiological dysmenorrhoea was made. The general practitioner prescribed painkillers in the form of non-steroidal anti-inflammatory drugs, which provided some benefit. However, the dysmenorrhoea continued to disrupt the patients life, and she was eventually referred to the gynaecologist. Pelvic examination by the gynaecologist revealed tenderness over the utero-sacral ligaments and on cervical movement. A transvaginal ultrasound scan revealed no pelvic abnormality. The gynaecologist made a provisional diagnosis of endometriosis and prescribed combined oral contraceptive pill (COCP). Three months later, the patient reported a significant improvement of her pain, but continued to experience some degree of dysmenorrhoea. She was therefore advised to tricycle the pill.
PRESENTATION
What Are the Main Presenting Symptoms for Endometriosis?
The main presenting symptoms of endometriosis
Dysmenorrhoea is the most common presenting symptom, affecting up to 80% of women with endometriosis
include chronic pelvic pain and infertility. Patterns of chronic pelvic pain caused by endometriosis include dysmenorrhoea, non-cyclical pelvic pain, and dyspareunia. The pain may also be associated with other cyclical symptoms, particularly related to the involvement of the urinary or gastrointestinal (GI) tract with endometriosis. The severity of these symptoms does not necessarily correlate with the extent of the disease when diagnosed at laparoscopy, as mild disease can cause severe symptoms. On the other hand, about 20% of women with advanced endometriosis have no symptoms.
GYNAECOLOGY
I GYNAECOLOGY Peer Reviewed
Dysmenorrhoea: this is the most common presenting symptom, affecting up to 80% of women with endometriosis. It is often described as severe and debilitating and does not respond to simple analgesia. The pain classically starts 12 weeks before the onset of menstruation and gradually worsens, reaching a peak in severity during the first 2 days of the menstrual flow. The pain then gradually lessens until it disappears at the end of the period. Non-cyclical pelvic pain: this affects up to a third of patients with endometriosis. It is often associated with adhesions, large ovarian endometriomas, peritoneal inflammation, and bladder or bowel endometriosis. Pain resulting from pelvic adhesions is usually provoked or worsened by certain body movements. Other pains may be triggered by ovulation, bowel movements (dyschezia), or urination. All types of non-cyclical pains often worsen around the time of menstruation. Deep dyspareunia: this affects about a third of patients with endometriosis and is mainly seen in advanced disease with deep infiltrating nodules. It may be severe enough to force the patient to abstain from intercourse. The pain is usually described as a stabbing pain on deep penetration. It is triggered by pressure on the scarred utero-sacral ligaments, recto-vaginal nodules or adhesions obliterating the pouch of Douglas, or involving the ovaries. The symptoms are typically worse before menstruation.
Endometriosis is defined as the presence of endometriallike tissue outside the uterine cavity, leading to a chronic inflammatory reaction.
tendance in adolescents is suggestive of endometriosis. The presence of the classical patterns of pain described above has a sensitivity of 76% and a specificity of 58% in detecting endometriosis. Around 30% of adolescents with chronic pelvic pain have endometriosis. Adolescents with pelvic pain not responding to analgesia and/or the COCP have about a 70% prevalence of endometriosis. Analysing the pattern of pelvic pain is crucial in establishing the diagnosis of endometriosis in adolescents. A pain diary documenting the frequen-
DIAGNOSIS
How Would You Diagnose Endometriosis in cy and character of the pain will help to determine whether the pain is cyclical and if it is related to Adolescents?
Symptoms: adolescents with endometriosis often present with acyclic and/or cyclic pelvic pain. Bowel and bladder symptoms are also common in this group of patients. Chronic pelvic pain severe enough to disrupt normal activities and school atbowel or bladder function. A family history of endometriosis is correlated with a higher likelihood of endometriosis in these patients. Although, endometriosis is the commonest cause of chronic pelvic pain in adolescents, other
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Box 1. Presenting symptoms Severe dysmenorrhoea Chronic pelvic pain Deep dyspareunia Cyclical or peri-menstrual symptoms of the bowel or bladder with possible abnormal bleeding or pain (eg, dyschezia) Infertility causes such as sexual abuse, ovarian tumour or genital tract anomalies, eg, imperforate hymen should be considered. Examination: pelvic examination, which may not be possible in adolescents, does not usually reveal specific signs in most patients with endometriosis. However, this examination is important mainly to rule out other causes of chronic pelvic pain such as ovarian tumour or genital tract anomalies. In adolescents who are not sexually active, bimanual rectalabdominal examination may be considered as it is better tolerated than a bimanual vaginal abdominal examination. A number of signs can be detected in some patients with endometriosis, including thickening, nodularity and tenderness over of the uterus, and fullness or a mass in the pouch
scan is useful in detecting endometriomas; however, endometriomas are rarely seen in adolescents. Magnetic resonance imaging is of value in identifying the presence and the extent of deeply infiltrating lesions. It may also help in detecting bowel and ureteric involvement. Laparoscopy: this is the gold-standard for the diagnosis of endometriosis. However, in adolescents, this procedure should only be considered in patients with disabling pain not responding to analgesia and/or the COCP. Ideally, a laparoscopic surgeon competent in managing endometriosis surgically should perform the procedure. The surgeon should also be comfortable operating on adolescents and be familiar with all the various morphologies of endometriosis. Clear, red, white, and/or yellow-brown lesions are more frequently found in adolescents than black or blue lesions. The procedure carries a 3% risk of minor complications and a 0.61.8/1,000 risk of major complications such as bowel perforation and vascular damage (Box 1).
MEDICAL TREATMENT OF the uterosacral ligaments, fixation and retroversion ENDOMETRIOSIS IN ADOLESCENTS
What Are the Available Medical Treatment Options That You Would Like to Discuss naecological and non-gynaecological conditions With This Young Patient?
of Douglas. Differential diagnosis: this includes all gythat cause chronic pelvic pain. Gynaecological disorders include primary dysmenorrhoea, sexual abuse, ovarian cysts/tumours, and genital tract anomalies. In sexually active adolescents, pelvic adhesions should also be considered (due to a previous pelvic inflammatory infection) in the differential diagnosis. Non-gynaecological diseases to be considered in the differential diagnosis include irritable bowel syndrome, inflammatory bowel disease, interstitial cystitis, and musculoskeletal pain. Imaging: this is of limited value in the diagnosis of endometriosis. A transvaginal ultrasound
Non-hormonal medical therapy (analgesia): empirical treatment with analgesics for chronic pelvic pain with a pattern suggestive of endometriosis (without a definitive diagnosis) should be considered as a first-line treatment option in adolescents. Non-steroidal anti-inflammatory drugs (eg, mefenamic acid or diclofenac) can be effective. The administration of these medications should be limited to episodes of pains lasting for a few days, eg, dysmenorrhoea. Hormonal therapy: 1. The COCP is a good choice for adolescents with
GYNAECOLOGY
possible endometriosis and can be used as an alternate first-line therapy. It improves dysmenorrhoea and offers a reliable method of contraception. COCP is generally well tolerated, safe, and inexpensive. Another advantage of the pill is that it can be used as long-term therapy. Tricycling the pill reduces the number of bleeds and the associated pain. Possible side effects include weight gain, headaches, nausea, breast enlargement, and depression. Patients should be warned about the increased risk of thromboembolism during COCP administration.
Box 2. Factors to consider when planning endometriosis treatment Age Need to preserve fertility Need for contraception Presenting symptoms (pain, infertility) Severity of pain and impact on quality of life Type, extent and location of endometriotic lesions Involvement of other non-gynaecological systems Expertise of clinician Availability of resources Patients preference
Box 3. Management options
Medical

Non-hormonal: simple analgesia (paracetamol, NSAID, codeine) Hormonal treatment: COCP, progestogens, GnRH analogues
The empirical use of GnRH agonists in adolescents without a definitive diagnosis of endometriosis is controversial
Surgery

Conservative: excision or ablation of endometriotic deposits, excision or ablation of ovarian endometriomas and excision of deep infiltrating endometriosis Radical: TAH BSO
BSO= bilateral salpingo-oophorectomy; COCP = combined oral contraceptive pill ; GnRH = gonadotrophin-releasing hormone; NSAID = non-steroidal anti-inflammatory drug; TAH = total abdominal hysterectomy.
laparoscopy may be necessary to plan long-term management of endometriosis, which is potentially a progressive disease with no cure (Boxes 2 and 3).
CASE 2
A 38-year-old woman presented to the gynaecol2. Gonadotrophin-releasing hormone (GnRH) agonists: the empirical use of GnRH agonists in adolescents without a definitive diagnosis of endometriosis is controversial. Although, it may help to avoid laparoscopic surgery, GnRH agonists could adversely affect the final bone density formation, particularly in patients younger than 17 years. Furthermore, a definitive diagnosis and staging with ogy outpatient clinic with a 12-month history of worsening intermittent lower abdominal and pelvic pain, and severe dyspareunia. The pains were severe enough to disrupt her life and sexual relationship. A recent severe episode of the pain led to an emergency admission to the hospital. She had no previous surgery and had completed her family, having had one child delivered vaginally in the past.
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In the diagnosis of endometriosis, a pelvic examination is important to rule out other causes of chronic pelvic pain.
Pelvic examination revealed tenderness affecting the right adnexa and the pouch of Douglas. She underwent a laparoscopy, which revealed widely spread deposits of active peritoneal endometriosis affecting both ovarian fossae, the utero-sacral ligaments, the pouch of Douglas, and the utero-vesical peritoneal fold. Extensive adhesions were also present between the bowel and anterior abdominal wall. All endometriotic deposits were ablated with electro-diathermy, and the adhesions were divided with scissors. At post-operative follow-up, her pain and dyspareunia were much improved. However, 6 months later she experienced a recurrence of her symptoms. She was then counselled regarding further management options and decided to take a 6-month course of GnRH agonist. This improved her pain dramatically, and she found the side effects manageable. However, a few months after the
completion of GnRH agonist therapy, the symptoms started to recur. The patient returned to clinic requesting a hysterectomy as a more definitive treatment for her pain.
MEDICAL MANAGEMENT What Is the Current Role of GnRH Agonists in Endometriosis? How Do GnRH Agonists Work and What Should You Warn the Patient About? How Can You Treat Potential Side Effects and How Long Would You Prescribe the Treatment for?
GnRH agonists are usually offered as a second-line medical therapy for endometriosis in patients with severe symptoms not responding to analgesics or COCP. They are also a good option for women experiencing persistence or recurrence of severe symp-
GYNAECOLOGY
toms after conservative surgery as is in our case. GnRH agonists cause an initial stimulation of the GnRH receptors on the gonadotrophs of the anterior pituitary gland, followed by inhibition due to loss of these receptors (known as receptor downregulation). The resulting fall in follicle-stimulating hormone leads to a pseudo-menopausal status with
majority of patients will experience a recurrence of symptoms few months after discontinuation of treatment. GnRH agonists are given as injections either on a monthly or 3-monthly basis. Side effects include menopausal symptoms of hot flushes, night sweats, mood changes, and vaginal dryness. The most worrying potential side effect is a 56% loss of bone mineral density. This limits the safe use of GnRH agonists to 6 months. The bone loss usually recovers partially after 612 months of discontinuation of GnRH agonists. The hypo-oestrogenic side effects and bone mineral loss can be significantly reduced by the daily administration of tibolone
Surgery is more effective in reducing pain in patients with more advanced endometriosis
2.5 mg as an add-back therapy. In some patients, it may be necessary to continue the GnRH agonist therapy beyond 6 months (unlicensed use). It is recommended in these cases to monitor bone density on a yearly base.
CONSERVATIVE SURGERY
Compared with medical therapy, surgery offers a more definitive treatment of endometriosis and tends to achieve longer lasting improvement of symptoms. The principles of surgical treatment of endometriosis include ablation, vaporization or excision of peritoneal implants, excision or ablation
oestrogen deficiency due to ovarian suppression. Prolonged oestrogen deficiency eventually causes atrophy of the ectopic endometrial tissue with subsequent relief of pain. The initial stimulation often causes worsening of the symptoms during the first 2 weeks of treatment. Patients may also experience irregular bleeding during the first 2 months of GnRH agonist therapy, but amenorrhoea then usually ensues. About 80% of patients start to experience improvement or complete relief of pain about 4 weeks after the initiation of treatment. This improvement will continue throughout the 6-month course of GnRH analogue therapy. However, the
of endometriomas, excision of deep infiltrating nodular endometriosis, and restoration of pelvic anatomy by adhesiolysis. The reported incidence of disease recurrence at 5-year follow-up is about 20% for surgery compared with about 50% for medical treatment. However, about 30% of patients will not experience any improvement in symptoms after surgery. Also of note is that surgery is more effective in reducing pain in patients with more advanced endometriosis. A laparoscopic approach for endometriosis surgery is superior to laparotomy as it allows a more thorough inspection of the pelvis with higher
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Surgery offers a more definitive treatment of endometriosis than medical therapy.
and atypical forms of pelvic endometriosis. Typical peritoneal implants are pigmented lesions including dark powder-burn, black puckered, brown, blueblack, and yellow deposits. Atypical non-pigmented lesions include clear, white or red polypoid or flame-like lesions. Other lesions include defects (windows) in the peritoneum. Ovarian endometriomas are thick-walled unilocular or multilocular cysts of varying sizes (usually < 12 cm in diameter) containing chocolate-coloured fluid due to repeated bleeding from the endometriotic tissue. They are typically associated with advanced endometriosis
A laparoscopic approach for endometriosis surgery is superior to laparotomy as it allows a more

magnification, allowing the detection of subtle endometriotic lesions. In addition, laparoscopic surgery minimizes trauma to tissues, resulting in less post-operative adhesion formation. Laparoscopy is also associated with less blood loss, and with its magnification it allows good detection and control of small bleeders. From the patients perspective, laparoscopic surgery shortens hospital stay and allows quicker return to normal activities. The stage and severity of endometriosis should be assessed and documented at laparoscopy by describing the findings and using the revised American Fertility Society classification system (stages IIV). Systematic inspection of the whole pelvis and abdominal cavity is essential. The laparoscopic surgeon should be familiar with the different typical
thorough inspection of the pelvis with higher magnification
and extensive adhesions between the affected ovary and pelvic sidewall, back of the uterus, and broad ligament. However, about 12% of endometriomas are not associated with adhesions or severe disease. Deep infiltrating endometriosis (> 5 mm depth of infiltration) usually affects the recto-vagi-
GYNAECOLOGY
nal septum and uterosacral ligaments. Utero-sacral ligament endometriosis is usually characterized by thickening and firmness of the ligament with visible scarring. It is therefore necessary to palpate the utero-sacral ligament either with the end of a blunt laparoscopic probe or by vaginal examination. Obliteration of the pouch of Douglas occurs when the affected rectum is pulled upwards and becomes fixed to the back of the uterus, causing partial or complete obliteration of the pouch of Douglas. Minimal-to-mild peritoneal endometriosis can either be excised or ablated with electro-coagulation or laser vaporization. Care should be taken to avoid thermal damage to the ureters when treating the pelvic sidewall. Both ablation and excision of mild endometriotic implants have been shown to be equally effective in improving post-operative pain. Deep infiltrating endometriosis affecting the utero-sacral ligaments and/or recto-vaginal septum should be completely excised.
Box 4. Indications for surgery for endometriosis Endometriosis detected during diagnostic laparoscopy Presence of an endometrioma > 3 cm Deep infiltrating disease causing significant symptoms Endometriosis associated with severe symptoms in subfertile patients After failure of medical treatment to control symptoms
CASE 3
A 26-year-old lady presented with a long-standing history of severe dysmenorrhoea and dyspareunia. The pattern of dysmenorrhoea was typical of endometriosis (as described above). She had been trying to conceive for the previous 15 months without success. She had also been troubled with indigestion and constipation. Her GI symptoms gradually worsened until she became unable to have solid food and survived on fluids only. As a result, her weight dropped dramatically from 58 to 38 kg over a period of 6 months. Pelvic examination revealed a fixed and retroverted uterus, but no recto-vaginal nodules were found. A transvaginal ultrasound scan showed a thick-walled, 7-cm, right ovarian cyst with internal echoes, suggestive of an endometrioma. A diagnostic laparoscopy was performed and showed grade IV endometriosis with extensive adhesions involving the bowel and completely covering the pelvic organs. Only the superficial part of a right-sided ovarian cyst was seen firmly adherent to the bowel, uterus, and abdominal wall. The tubes and ovaries could not be visualized. In view of the extent and severity of the endometriosis and the involvement of the bowel, no treatment was performed on that occasion. Post-operatively, a magnetic resonance imaging scan was performed showing an 8-cm multiJPOG MAY/JUN 2012 101
RADICAL SURGERY
This includes total abdominal hysterectomy with or without bilateral oophorectomy. This treatment option should only be considered in patients who have completed their family and have had failed medical or conservative surgical treatments. A preoperative trial of GnRH analogues may be helpful in determining whether this treatment will be successful and whether oophorectomy should also be performed. All deep-seated endometriosis should be removed during the hysterectomy to prevent remaining disease from causing persistent pain. Bilateral salpingo-oophorectomy may result in a better pain relief with reduced chances of further surgery in the future. However, this benefit has to be balanced against the disadvantage of inducing menopause with the need of hormone replacement therapy (HRT), especially in patients under 40 (Box 4).
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Practice points
the endometriosis. Two months after surgery, the patient recovered very well, and all her pain and GI symptoms have completely resolved. She was able to eat normally and gradually gained weight. At this stage, she was referred to have in vitro fertilization (IVF) treatment.
Careful assessment of the pattern of chronic pelvic pain together with laparoscopy is the key to establishing an accurate diagnosis of endometriosis. Treatment should be tailored according to patients age, disease severity and extent, fertility requirements, contraception, and patients wishes. In adolescents with symptoms of endometriosis, empirical treatment with analgesics and/or combined oral contraceptive pill (COCP) is recommended before resorting to laparoscopy. Gonadotrophin-releasing hormone (GnRH) agonists may adversely affect the final bone density formation in adolescents especially those under 17. First-line hormonal treatments include the COCP and continuous progestogens. Second-line medical treatment includes GnRH agonists. Conservative surgical treatment reduces pain, improves fertility, and offers a more definitive treatment with less chances of recurrence.
SURGERY FOR EXTENSIVE DISEASE

What Is the Importance of Pre-operative Assessment?
Pre-operative assessment helps to achieve an accurate diagnosis of the stage of the disease and to assess patients fitness for the surgery. This will help to choose the best surgical approach and to anticipate possible difficulties. In patients with suspected deep infiltrating endometriosis, it is important to exclude ureteric, bladder or bowel involvement.
locular cyst on the right ovary with several pelvic deposits of endometriosis involving the bowel. In view of the bowel involvement with endometriosis and the severe GI symptoms, the patient was reviewed by a colorectal surgeon who discussed various surgical options for bowel endometriosis. The patient was also counselled about the possible need of a colostomy. The patient was offered conservative surgery through laparotomy for her extensive endometriosis. The procedure was carried out jointly with the colorectal surgeon.
A magnetic resonance imaging scan is of value in determining the extent of deeply infiltrating lesions and the involvement of bowel and bladder. Other investigations of value may be a contrast enema and intravenous urogram. The management of deeply infiltrating lesions is very complex. Patients should be referred to centres with the necessary expertise and a multidisciplinary team should be involved in the treatment. Pre-operative bowel preparation should be considered.
What Is the Association Between EndomeAt laparotomy, extensive adhesiolysis was car- triosis and Infertility and What Treatment ried out freeing the bowel, uterus, tubes, and ova- Option Should You Offer These Patients?
ries. The right ovarian endometrioma was opened and drained. The cyst wall was then stripped off and sent for histology. A large segment of the colon was found to be affected by the disease. A hemicolectomy was therefore performed. Interestingly, the histological examination of the resected colon revealed coexisting Crohns disease in addition to
Infertility: 3040% of women with endometriosis suffer from infertility. The mechanism of infertility in mild endometriosis is not fully understood. In moderate-to-severe endometriosis, infertility results from anatomical distortion of the fallopian tubes and the tubo-ovarian relationship due to adhesions.
GYNAECOLOGY
Medical treatment of endometriosis does not improve fertility. Surgery, on the other hand can improve fertility in women with moderate-to-severe endometriosis. Subfertile women with severe endometriosis who have minimal or no symptoms are better treated with IVF, which gives them a higher pregnancy rate than surgery. On the other hand, subfertile women with severe symptoms or who have large endometriomas should be offered surgery. Post-operative hormonal treatment has no beneficial effect on pregnancy rates after surgery. However, down-regulation with GnRH analogues after debulking surgery for stage IIIIV disease may be required prior to IVF. If satisfactory anatomical restoration has been achieved with surgery, the patient could be advised to try to conceive naturally for 612 months before resorting to IVF. If the anatomical outcome of surgery is suboptimal, IVF should be considered shortly after surgery.
proaches to endometriomas, including excision or ablation of the cyst wall after drainage and irrigation. Most surgeons would excise the cyst wall as this has been shown to be superior to ablation with fewer recurrences. Excision of the cyst is achieved by stripping the cyst wall off from the underlying ovarian tissue. Bleeding points are then secured
The optimal type of surgery for endometriomas remains controversial
How Would You Treat an Endometrioma Seen on Scan?

The management of endometriomas in patients receiving fertility treatment is controversial. Whilst some reproductive specialists believe that endometriomas (> 3 cm) should be treated surgically before assisted reproductive treatment, others argue that surgery could significantly damage ovarian reserve, which could consequently compromise success of treatment. On the other hand, advocates of surgery claim that untreated endometriomas could adversely affect ovarian response to follicle-stimulating hormone stimulation and could make egg retrieval difficult. In addition, inadvertent insertion of the egg retrieval needle into an endometrioma could cause severe pelvic infection with abscess formation. However, most fertility specialists would surgically treat very large endometriomas (> 8 cm). The optimal type of surgery for endometriomas remains controversial. There are two main surgical apwith diathermy. Ablation of the cyst could be achieved by laser vaporization or electrocoagulation of the inner cyst wall. Simple aspiration of the endometrioma is not sufficient as it is associated with a high recurrence rate. A biopsy of the cyst wall should always be sent for histology to exclude rare cases of malignancy.
How Should Dyspareunia Caused by Severe Recto-vaginal Endometriosis Be Treated?

Surgery is usually the only effective treatment for women with severe debilitating symptoms due to recto-vaginal endometriosis, which do not usually respond to medical therapy. Surgery for rectoJPOG MAY/JUN 2012 103
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vaginal septum endometriosis is very difficult and requires considerable skill and experience. Traditionally, this surgery has been performed through laparotomy. However, more recently, a laparoscopic approach has been developed in a few centres. Whilst laparoscopy offers several advantages over open surgery, it takes a considerably longer time, which increases the risk of compartment syndrome (an acute calf muscle ischaemia due to prolonged pressure within the confined fascial compartment leading to muscle necrosis). In addition to reducing the operating time, open surgery allows careful palpation for nodular disease, which is necessary for accurate determination of the extent of the disease. This type of surgery is usually carried out jointly with a colorectal surgeon (and sometimes an urologist) who may not be comfortable performing this complicated surgery laparoscopically. The recto-vaginal space is accessed by mobilizing the rectum and the nodules removed until normal tissue is identified. Depending on the extent of rectal involvement, removal of endometriotic tissue from the rectum can be achieved by shaving the anterior wall, disc resection, anterior wall resection, or segment resection. Occasionally, a temporary co-
lostomy may be necessary in severe cases.
CONCLUSION
Endometriosis can be a very complex condition to treat, and it is important to tailor the treatment to the individual patient. As we have seen, medical treatment may be a very good option for an adolescent like Case 1 but would not be appropriate in someone seeking to get pregnant like Case 3. More invasive treatment is necessary if the initial conservative therapy is not effective or if the disease is more advanced. Again, in these cases, patients wishes must be kept into consideration. A hysterectomy, although a good option for Case 2, would not be appropriate for Case 1 or 3.
2011 Elsevier Ltd. Initially published in Obstetrics, Gynaecology & Reproductive Medicine 2011; 21(4):112117.
About the Authors

Francesca Raffi is a Clinical Research Fellow at Royal Derby Hospital, Derby, UK. Saad Amer is Associate Professor of Obstetrics and Gynaecology at Royal Derby Hospital, Derby, UK.
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Hyperemesis, Gastrointestinal and Liver Disorders in Pregnancy

Clare Cuckson, BA, MB BChir, MRCOG; Sarah Germain, MA, MB BS, DPhil, MRCP
PHYSIOLOGICAL CHANGES IN PREGNANCY

During pregnancy, there is generalized relaxation of smooth muscle resulting in relaxation of the oesophageal sphincter, reduced gastric peristalsis, and delayed gastric emptying. Small and large bowel transit times are increased. There is increased blood flow to the liver and increased production of fibrinogen, transferrin and many other binding proteins. Reference ranges for many liver function tests are altered. Gestation-specific alkaline phosphatase is increased, mainly from increased placental production, and aminotransferases and -glutamyltransferase are reduced.
Nausea, Vomiting and Hyperemesis Gravidarum

Background: nausea is experienced by up to 90% of women during pregnancy, and 50% complain of vomiting. Symptoms can start from 5 weeks and usually resolve by the end of the first trimester. Persistent vomiting in pregnancy is termed hyperemesis gravidarum (HG) when the woman is unable to maintain adequate hydration and nutrition. The cause of HG is incompletely understood, but hormonal, mechanical and psychological factors have been implicated. Biochemical thyrotoxicosis (raised free thyroxine and suppressed thyroid-stimulating hormone [TSH]) is thought to occur by the stimulatory action of human chorionic gonadotrophin (hCG) on the thyroid (hCG shares a common -subunit with TSH). Features: signs of HG include weight loss, muscle wasting, ptyalism (inability to swallow saliva resulting in spitting and drooling) tachycardia, and postural hypotension. Biochemical findings may include hyponatraemia, hypokalaemia, abnormal thyroid funcJPOG MAY/JUN 2012 105
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Table 1. Differential diagnosis and relevant investigations of nausea and vomiting in pregnancy Urinary tract infection Renal failure (uraemia) Gastro-oesophageal reflux/gastritis/peptic ulcer disease Bowel obstruction Pancreatitis Diabetic ketoacidosis Addisons disease Hyperthyroidism CNS pathology; vestibular disorders, cerebral tumours Mid-stream urine U & Es Helicobacter pylori antibodies, endoscopy, try empirical proton pump inhibitor Plain abdominal X-ray (ultrasound can detect bowel dilatation and bowel tumours) Amylase, calcium, glucose Abdominal ultrasound, MRCP Glucose, U & Es, urinalysis for ketones, glucose tolerance test U & Es, early morning cortisol, short synacthen test TFTs, TSH receptor antibodies Neurological examination, CT/MRI brain
CNS = central nervous system; CT = computed tomography; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance imaging; TFT = thyroid function test; TSH = thyroid-stimulating hormone; U & Es = urea and electrolytes.
tion and liver function, and metabolic hypochloraemic alkalosis (loss of HCl from stomach). Complications: if inadequately treated HG can lead to significant maternal and fetal morbidity.
aspiration of vomitus.
Fetal
Severe HG (abnormal biochemistry and/or Wernickes) can result in intrauterine growth restriction or even intrauterine death, but overall there are lower risks of miscarriage, stillbirth and preterm delivery. Diagnosis & investigations: it is a diagnosis of exclusion, and other causes must be considered especially if the vomiting starts after the first trimester. The possible differential diagnoses of nausea and vomiting in pregnancy are given in Table 1. Management: a protocol for management of hyperemesis is given in Table 2. It is important to give the patient adequate reassurance as to the safety of anti-emetics in pregnancy as poor compliance is a major reason for failure of treatment. Mild cases can be managed as day cases, giving intravenous rehydration and anti-emetics, and continuing
Maternal
Severe hyponatraemia or its over rapid correction can lead to central pontine myelinolysis or osmotic myelinolysis (presents with confusion, horizontal gaze paralysis, and spastic quadriplegia). Wernickes encephalopathy (Vitamin B 1 deficiency) can occur in any condition of unbalanced nutrition, which lasts for 23 weeks. This presents with a triad of confusion, ataxia, and ophthalmoplegia. It carries a mortality of between 10% and 15%, and incomplete recovery can lead to Korsakoffs psychosis where the patient develops anterograde and retrograde amnesia and confabulation. Thromboembolism is a risk due to dehydration and immobility in hospital. Others include vitamin deficiencies and
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Table 2. Management of hyperemesis gravidarum
Investigations
Urea and electrolytes, full blood count, liver function tests, thyroid function tests, calcium Mid-stream urine Ultrasound scan pelvis 1 L 0.9% normal saline with 20 mmol potassium chloride over 2 hours 1 L 0.9% normal saline with 20 mmol potassium chloride over 4 hours Followed by 1 L 0.9% normal saline every 8 hours with potassium replacement dependant on serum level
Intravenous fluids
Vitamin supplements
Thiamine PO 50 mg TDS or 100 mg IV in 100 mL normal saline once weekly or B vitamins/vitamin C (contains 250 mg thiamine, riboflavin, pyridoxine, nicotinamide, and vitamin C) First-line: Cyclizine 50 mg PO/IM/IV TDS Second-line: Metoclopramide 10 mg PO/IM/IV TDS Promethazine 25 mg PO Nocte Domperidone 3060 mg PR BD or 10 mg PO QDS Prochlorperazine 5 mg PO TDS or 12.5 mg IM/IV TDS; 5 mg TDS PR or 25 mg OD PR
Anti-emetics
Thromboprophylaxis
Anti-embolic stockings Low-molecular-weight heparin, eg, enoxaparin 40 mg OD (< 90 kg) or 60 mg OD (> 90 kg)
BD = twice a day; IM = intramuscular; IV = intravenous; nocte = every night; PO = by mouth; PR = per rectum; QDS = four times a day; TDS = three times a day.
with buccal medication, or suppositories then oral once vomiting is under control. It is usual to advise continuing regular anti-emetics for 7 days following admission to prevent a recurrence of symptoms. Intravenous thiamine should be given to moderate to severe cases. Inpatients should be given anti-embolic stockings and low-molecular-weight heparin, and serum electrolytes should be checked daily. Refractory cases not responding to conventional anti-emetics should prompt further investigation for another cause, and a trial of corticosteroids should be considered. Biochemical thyrotoxicosis does not require treatment unless there are clinical signs of hyperthyroidism and TSH receptor antibod-
ies are present.
Gastric Reflux
Gastric reflux is a common condition affecting twothirds of pregnant women especially in the third trimester. It is exacerbated by changes in pregnancy, including pressure from the enlarging uterus, increased gastric transit time, and reduced lower oesophageal sphincter pressure. These lead to reflux of gastric contents into the lower oesophagus and inflammation of the mucosa. Features include retrosternal and epigastric pain, and dyspepsia. The differential diagnosis includes peptic ulcer disease. Management includes non-pharmacological
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The cause of hyperemesis gravidarum is incompletely understood.
Peptic Ulcer Disease

Peptic ulcer disease is uncommon in pregnancy, and this may in part be owing to a protective effective of oestrogens and prostaglandins on the gastric mucosa. It usually presents with epigastric pain. Complications such as haemorrhage and perforation are rare in pregnancy, but significant symptoms such as haematemesis should be investigated with upper gastrointestinal endoscopy, which can be safely performed in pregnancy. Pharmacological treatment includes H2-receptor blockers (eg, ranitidine) or proton-pump inhibitors (eg, omeprazole). Misoprostol is avoided, and Helicobacter pylori eradication can usually be delayed until after pregnancy.
Constipation
This is another common condition in pregnancy affecting 40% of women, as physiological changes lead to decreased colonic motility and pressure of the gravid uterus on rectosigmoid colon. Risk factors include dehydration, poor dietary intake, opiate analgesia, and iron supplements. Non-pharmacological measures such as increased fluid intake and dietary fibre are usually sufficient, with temporary cessation of oral iron. Laxatives may be required if these other measures fail, and both osmotic (lactulose, magnesium hydrochloride) and stimulant (senna, glycerol supposito(such as sleeping semi-recumbent and avoiding food and fluids immediately before bed) and pharmacological measures. Drugs that are safe to use constipation and magnesium diarrhoea); Antacids with alginic acid; metoclopramide; sucralfate; H 2receptor blockers (ranitidine is safe but avoid cimetidine because of its effect on androgen receptors); and proton-pump inhibitors. Avoid misoprostol as it is an abortifacient, and it is also associated with congenital abnormalities, fetal death, and uterine perforation.
ries) types are safe.
DISORDERS OF THE LIVER AND in pregnancy are antacids (aluminium salts cause BILIARY TRACT
There are several disorders of the liver, which are specific to pregnancy and are important to recognize as they are associated with significant morbidity and mortality for the mother and her fetus and delivery is the only cure. Some pre-existing conditions may only become clinically evident during pregnancy, and others such as hepatitis E have a
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predilection for pregnant women in whom the prognosis is significantly worse.
Table 3. Swansea criteria for diagnosis of AFLPa six or more of the following features in the absence of another explanation Vomiting Polydipsia/polyuria Abdominal pain Encephalopathy Elevated bilirubin (> 14 mol/L) Hypoglycaemia (< 4 mmol/L) Elevated urate (> 340 mol/L) Leucocytosis (> 11109/L) Ascites or bright liver on ultrasound scan Microvesicular steatosis on liver biopsy Elevated ammonia (> 47 mol/L) Elevated transaminases (aspartate aminotransferase or alanine aminotransferase > 42 IU/L) Renal impairment (creatinine > 150 mol/L) Coagulopathy (prothrombin time >14 s or activated partial thromboplastin time > 34 s)
a Chng CL, Morgan M, Hainsworth I, Kingham JG. Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut 2002 Dec;51:876880.
Liver Disorders Specific to Pregnancy

Haemolysis Elevated Liver Enzymes and Low Platelets (HELLP)
Background HELLP is thought to be a severe form of pre-eclampsia, affecting 520% of these pregnancies, with one-third post partum. Hepatic damage is thought to occur as a result of increased sinusoidal pressure, hypovolaemia, and fibrin deposition. Features and investigations the condition can be asymptomatic or present with right upper quadrant or epigastric pain, nausea, vomiting, and general malaise. In most cases, hypertension and proteinuria are present, and there is a mild to moderate elevation of aminotransferases and bilirubin. Blood film will reveal true thrombocytopenia and red cell fragments indicative of haemolysis. Complications HELLP is associated with significant maternal (1%) and perinatal (1060%) mortality. Maternal complications include liver infarction and rupture, subcapsular liver haematoma, acute renal failure, and placental abruption. Management the mainstay of management involves stabilizing the patient, including control of blood pressure and giving magnesium sulphate for prevention of eclampsia. Prompt delivery is usually required if it presents antenatally. Clotting times should be monitored and correction of thrombocytopenia (platelets, < 50 10 /L) is required to cover
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Acute Fatty Liver of Pregnancy
Background this rare disorder is associated with abnormalities in mitochondrial oxidation and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. There is considerable overlap of the symptoms and signs with pre-eclampsia and HELLP syndrome. It is more common in multiple pregnancies, primiparae, obese women, and with a male fetus. Features and investigations the presentation is similar to that in HELLP syndrome with nausea, vomiting and abdominal pain, although the rise in serum transaminases, creatinine and leucocytosis tends to be more marked. Other discriminating features are hypoglycaemia and coagulopathy, which are much more evident in acute fatty liver of pregnancy (AFLP). It may present post partum with severe haemorrhage. Table 3 gives the diagnostic criteria for AFLP. Complications AFLP carries a high maternal and fetal mortality of between 218% and
delivery. Studies vary on the recurrence rate of HELLP in a future pregnancy, with figures of 227% quoted. The risk of pre-eclampsia is higher and may be up to 75% if background hypertension is present. Many women choose not to have a further pregnancy.
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758%, respectively. Maternal complications include disseminated intravascular coagulation, renal failure, pancreatitis, and (transient) diabetes insipidus. There is also a risk of progression to hepatic encephalopathy and fulminant liver failure. Management if AFLP presents antenatally, then coagulopathy and hypoglycaemia should be treated aggressively and delivery expedited. High dependency unit and/or intensive therapy unit involvement are/is usually required and early liaison with a specialist liver unit in case of progression to liver failure. Post delivery, most women recover quickly, and management is conservative and supportive. Liver function may take up to 4 weeks to recover, and liver transplantation should be considered in those with liver rupture, severe encephalopathy, or failure of liver recovery. The recurrence rate for AFLP is around 25%, but many women avoid a further pregnancy. The baby should be screened for LCHAD deficiency.
Obstetric Cholestasis
with this condition are to the fetus and include preterm delivery, meconium staining of the liquor, and intrauterine fetal death, which is reported to be 212% depending on the studies reviewed. The risk of stillbirth is difficult to predict despite cardiotocography monitoring and ultrasound for fetal wellbeing. One prospective cohort study of 693 cases of OC has shown that the risk to the fetus occurs when the serum bile acids are above 40 mol/L and that there is a 12% increase in fetal complications for every 1 mol/L increase in the serum bile acid level.
The risk of stillbirth is difficult to predict despite cardiotocography monitoring and ultrasound for fetal wellbeing
Features
and
investigations
Obstetric
cholestasis (OC) is a pregnancy-specific condition, which occurs in approximately 0.7% of pregnant women in the UK, and the main features are maternal pruritus and impaired liver function. In most cases, the serum bile acids are elevated, but derangement in other markers of liver function such as transaminases, bilirubin and -glutamyltransferase also occurs. Other maternal symptoms include steatorrhoea, pale stools, and dark urine. The aetiology of the condition is incompletely understood but is thought to be due to the cholestatic effect of oestrogens, which is supported by the higher incidence in twin pregnancy and occurrence of similar symptoms in some individuals taking the oral contraceptive pill. Complications the major risks associated
Management involves excluding other causes for liver function derangement as OC is a diagnosis of exclusion. Itching can be severe, causing marked skin excoriation, insomnia, and maternal distress. It is important to take a proper history in these cases as a rash is not a feature of OC and the patient will report that the itching preceded the skin changes. Mild symptoms can be managed with antihistamines and emollients containing 12% menthol. For more severe cases, ursodeoxycholic acid is the most effective treatment for ameliorat-
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It is important to recognize the liver disorders that are specific to pregnancy because they are associated with significant morbidity and mortality for the mother and her fetus.
ing the symptoms and may improve the biochemical picture. It is not known whether treatment with ursodeoxycholic acid improves the outcome for the fetus or whether cases in which the serum bile acids are below 40 mol/L can be managed expectantly, and this is the subject of ongoing research. Vitamin K 10 mg orally should be given to the mother from time of diagnosis to delivery to reduce the risk of post-partum haemorrhage. Most units advocate delivery at around 3738 weeks, and one study examining 352 pregnancies complicated by OC found that over 90% of intrauterine deaths occurred after 37 weeks, which supports this practice. In resistant cases, rifampicin can be used under the guidance of a liver specialist although published data on its use in pregnancy is
limited. Maternal liver function tests usually return to normal post partum with no long-term liver damage, but should be monitored to ensure this happens. Women who have had OC should avoid the combined oral contraceptive pill. Recurrence risk of OC in a future pregnancy is high at > 90%.
Non-pregnancy-specific Liver Disease

Gall Bladder Disease (Gallstones and Cholecystitis)
Pregnancy increases the risk of gallstone formation, as oestrogen increases the cholesterol content of the liver and progesterone increases bile secretion. This results in increased saturation of the bile with
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Laxatives may be required if increased fluid intake and dietary fibre fail to relieve constipation in pregnancy.
tion, clotting, glucose, full blood count and oxygen saturation will help to distinguish those needing intensive care.
Viral Hepatitis
Viral hepatitis is caused by the hepatitis viruses A, B, C, D and E and by cytomegalovirus, Epstein-Barr virus and herpes simplex virus (HSV). The course of these viruses is usually unaffected by pregnancy except for hepatitis E and HSV where the outcomes are likely to be more severe. In general, patients may be asymptomatic or complain of right upper quadrant pain, nausea and vomiting, and general malaise. Transaminases are raised typically > 1,000 IU, but alkaline phosphatase is often normal.
cholesterol and gallstone formation. Cholecystitis should be treated promptly with broad-spectrum intravenous antibiotics and fluids, as it can precipitate pre-term labour. Pancreatitis is another serious complication of gallstones and again management is usually conservative as discussed below.
Pancreatitis
The course of these viruses is usually unaffected by pregnancy except for hepatitis E and HSV where the outcomes are likely to be more severe
Pancreatitis rarely occurs in pregnancy and is most commonly due to gallstones. Hypertriglyceridaemia and hypercalcaemia of primary hyperparathyroidism are other causes. The presentation and symptoms are similar to the non-pregnant patient, and the diagnosis is usually made when the serum amylase > 1,000 U/L. Management is supportive with intravenous fluids and analgesia. Most cases will resolve spontaneously, but around 10% will develop severe complications needing intensive therapy unit support. Careful assessment of renal and liver funcJPOG MAY/JUN 2012 112
Hepatitis A transmission of hepatitis A occurs by the faecooral route and is common in parts of Asia, Africa and South America where sanitation is poor. It should be suspected if there is a history
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of recent travel to these areas. Most cases are selflimiting, but fulminant liver failure can occur. Acute infection is confirmed by the presence of hepatitis A IgM antibodies in the serum. Vertical transmission at delivery is rare, but if occurs the neonate can be treated with normal immunoglobulin. Hepatitis B transmission of hepatitis B occurs mainly by sexual contact or infected blood products. Acute infection usually presents with mild symptoms. Fulminant liver failure can occur in around 1%. Usually less than 5% remain as carriers which is associated with a risk of cirrhosis, chronic active hepatitis, and liver cancer. The risk of vertical transmission is low unless the mother develops the acute infection during the pregnancy (90% in the third trimester). High vertical transmission rates also occur in mothers who are positive for the hepatitis B e antigen which is a marker of high infectivity. Mode of delivery does not alter the vertical transmission rate. Invasive procedures in labour, such as applying fetal scalp electrodes or fetal blood sampling, should be avoided. Neonates should be given hepatitis B immunoglobulin and vaccinated at birth and usually again at 1 month and 6 months. Giving this combined regimen protects against neonatal infection in 93% of cases. Breastfeeding should be encouraged as this also does not alter the risk of neonatal infection provided vaccination is given. Mothers with hepatitis B should also be screened for hepatitis C and human immunodeficiency virus and have their baseline liver function checked. Hepatitis C Hepatitis C is a blood-borne infection and is common amongst intravenous drug users. At least 85% of infected individuals will develop chronic liver disease with around 30% developing cirrhosis after 10 years. Women should be under the care of a hepatologist.
Table 4. Differential diagnosis of abnormal liver function in pregnancy Viral hepatitis (A, B, C, E) EBV, CMV, HSV Autoimmune hepatitis Primary biliary cirrhosis Autoimmune sclerosing cholangitis Wilsons disease Haemochromatosis Gallstones Fatty liver Cirrhosis Serology ANA, anti-LKM antibodies Anti-mitochondrial antibodies, ANF, anti-sm Anti-sm, ANCA Serum copper and caeruloplasmin Ferritin Ultrasound
ANA = antinuclear antibodies; ANCA = anti-neutrophil cytoplasmic antibodies; ANF = antinuclear factor; CMV = cytomegalovirus; EBV = Epstein-Barr virus; HSV = herpes simplex virus; LKM = liver-kidney microsome.
Pregnancy has no effect on the disease; however, patients are more at risk of OC which is often more severe. The risk of vertical transmission is low if the mother has a low viral titre. Mode of delivery and breastfeeding do not influence the rate of neonatal infection. Hepatitis E Hepatitis E is spread by the faecooral route and, in the non-pregnant population, is usually a self-limiting illness. Pregnant women are more severely infected with 20% developing acute liver failure. The maternal mortality rate is 12 times higher than in the non-pregnant population. Vertical transmission was approximately 30% in one small study with a fetal mortality rate of 50% in those affected. Herpes Simplex Virus HSV hepatitis occurs more commonly in pregnant women than the general population and has a maternal mortality rate of 39%. It can occur through primary infection or by reactivation of a latent disease and can be caused by serotypes HSV 1 and 2. Mucocutaneous lesions
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are present in only 50% of cases. Definitive diagnosis is made on liver biopsy, but computed tomographic scan is of value, showing multiple low-density areas within the liver. Treatment with aciclovir improves survival and should not be delayed if the diagnosis is suspected. The differential diagnosis of abnormal liver function in pregnancy and a guide to investigations are given in Table 4.
hood. The incidence of ulcerative colitis is higher in women than in men whereas Crohns disease affects both sexes equally. The course of disease is usually unaffected by pregnancy, although Crohns may flare post partum. Symptoms suggestive of active disease should be investigated with full blood count, serum albumin level and stool culture, and sigmoidoscopy or proctoscopy.
PREGNANCY FOLLOWING LIVER TRANSPLANTATION

The chance of successful pregnancy in women following transplantation is around 70%, although the risk of complications such as miscarriage, intrauterine growth restriction, pre-term delivery and pre-eclampsia is increased. Ideally, pregnancy should be deferred until at least 1 year following liver transplantation to allow the graft function to stabilize and when lower doses of immunosuppressants can be used. Also, there is an increased risk of infection with cytomegalovirus immediately follow transplantation, which may result in congenital abnormalities if it occurs in early pregnancy. Graft function and survival are not affected by pregnancy though. The immunosuppressant agents, tacrolimus, prednisolone and ciclosporin, are generally well tolerated in pregnancy and are not associated with fetal malformations. Mycophenolate mofetil is teratogenic in animals, and there are reported cases of congenital malformations in babies born to mothers taking this drug and it therefore should be avoided. Rates of caesarean section are high amongst this group of women although vaginal delivery is not contraindicated. Management: obstetric outcome is related to disease activity at the time of conception, and women should be encouraged to conceive during periods of remission. Active disease is a risk factor for pre-term delivery and low birth weight. The management of IBD during pregnancy is frequently compromised owing to patient fears regarding congenital malformations and sometimes similar concerns or lack of experience of physicians in dealing with pregnant women. In general, attacks should be
The management of IBD during pregnancy is frequently compromised
Inflammatory Bowel Disease

Features and investigations: inflammatory bowel disease (IBD) usually presents in young adultJPOG MAY/JUN 2012 114
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managed the same as in the non-pregnant patient. The aminosalicylates, sulfasalazine and mesalazine, are safe for use throughout pregnancy and breastfeeding. Sulfasalazine is a dihydrofolate reductase inhibitor, which blocks the conversion of folate to its more active metabolites; therefore, supplementation with 5 mg folic acid is advised preconceptually and during pregnancy. Corticosteroids are also safe although there is some evidence for an increased risk of cleft lip and palate in animals and humans. For acute colonic disease, topical steroid enemas can be used. Prednisolone is the corticosteroid of choice as > 90% is metabolized by the placenta, thus lowering the amount reaching the fetus. There is extensive data on the safety of azathioprine in pregnancy, and there are no harmful effects on the fetus when adequate doses are used. Second-line immunosuppressants such as 6-mercaptopurine as well as metronidazole and vitamin B12 can also be used safely. Conversely, methotrexate is contraindicated because of teratogenicity, and patients should be advised not to conceive within 3 months of taking this drug. Infliximab is a chimeric monoclonal antibody against tumor necrosis factor- and has revolutionized the course of refractory IBD. In a case series of 96 pregnant women with Crohns disease or rheumatoid arthritis treated with infliximab, the pregnancy outcomes were not different between the two groups or compared with the general population. A small study in breastfeeding mothers has also shown that infliximab was undetectable in the breast milk and in the sera of newborn infants. Mode of delivery: most women with IBD can deliver normally. Indications for Caesarean section include active or severe perianal disease and ileoanal pouch anastomosis. Where surgery has been performed, it is recommended that the obstetrician
Practice points Hyperemesis gravidarum is a serious condition and requires prompt treatment with hydration, anti-emetics and thiamine to prevent complications. HELLP syndrome and acute fatty liver of pregnancy are associated with high maternal and fetal morbidity, and cases should be managed by senior clinicians. Obstetric cholestasis is a diagnosis of exclusion, and other causes of liver disease should be considered. Hepatitis E and herpes simplex virus can be more severe in pregnancy. Inflammatory bowel disease is usually unaffected by pregnancy; and in general, flares should be managed in the same way as in the non-pregnant patient. Presentation of appendicitis may be atypical in pregnancy and may delay the diagnosis.
obtain information from the surgeon to define the risks of vaginal delivery. Coeliac disease: this is an abnormality of the small intestinal mucosa caused by the ingestion of gluten-containing substances in susceptible individuals. Diagnosis is made by jejunal or duodenal biopsy, which shows subtotal villous atrophy. Up to 80% of patients are positive for HLA B8, and there is a familial link. Features include diarrhoea, malabsorption, anorexia, and weight loss. Haematological disorders are common, and other complications include osteoporosis and osteomalacia due to malabsorption of vitamin D and calcium, muscle weakness, peripheral neuropathy, encephalopathy, and other mineral and vitamin deficiencies (vitamin B 6, B12, zinc, folate, ferritin). Exacerbation of symptoms may occur in pregnancy, and the rates of miscarriage and stillbirth are increased in those with untreated disease. Strict adherence to a gluten-free diet can reduce poor fetal outcomes. Careful attention must be paid to replacing essential minerals and vitamins, and women should be encouraged to breastfeed as this can reduce the incidence or delay the onset of coeJPOG MAY/JUN 2012 115
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liac disease in the neonate in those with a strong family history.
FURTHER READING
Bottomley C, Bourne T. Management strategies for hyperemesis. Best Pract Res Clin Obstet Gynaecol 2009;23:549564. Caprilli R, Gassull MA, Escher JC, et al. European Crohns and Colitis Organisation. European evidence based consensus on the diagnosis and management of Crohns disease: special situations. Gut 2006;55(suppl 1):i36 i58. Chng CL, Morgan M, Hainsworth I, Kingham JG. Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut 2002;51:876880. Joshi D, James A, Quaglia A, Westbrook RH, Heneghan M. Liver disease in pregnancy. Lancet 2010;375:594605. McKillop L, Williamson C. Liver disease in pregnancy. Postgrad Med J 2010;86:160164. Nelson Piercy C. Handbook of Obstetric Medicine. Informa Healthcare; 2009:241261. Nelson-Piercy C, Williamson C. Gastrointestinal and hepatic disorders. In: Greer IA, Nelson-Piercy C, Walters B, eds. Maternal medicine. London: Churchill Livingstone; 2007:171190. Royal College of Obstetricians and Gynaecologists. Green top guideline number 43, January 2006. Sibai BM. Imitators of severe preeclampsia. Obstet Gynecol 2007;109:956966. Williamson C, Hems LM, Goulis DG, et al. Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. BJOG 2004;111:676681.
Appendicitis
The incidence of appendicitis in pregnancy is similar to that in the non-pregnant population (1 in 5001,500). Presentation may be atypical in pregnancy and therefore the diagnosis may be delayed. The appendix is shifted superiorly and therefore classic pain over McBurneys point may be absent. Vomiting may be the only symptom. Leucocytosis is common in pregnancy, and symptoms such as fever or extreme leucocytosis are suggestive of perforation. Ultrasound has high sensitivity and specificity for the detection of appendicitis although clinical assessment should be used to guide management. Broad-spectrum antibiotics should be given preoperatively. Prompt diagnosis and treatment are mandatory as the perinatal death rate is 20% in cases of perforation. Pre-term labour occurs in 11% of cases in the second trimester, and this risk decreases considerably in the first week after surgery.
2011 Elsevier Ltd. Initially published in Obstetrics, Gynaecology & Reproductive Medicine 2011;21(3):8085.
About the Authors

Clare Cuckson is a Specialist Registrar Obstetrics at Queen Charlottes and Chelsea Hospital, London, UK. Sarah Germain is a Specialist Registrar in Obstetric Medicine/Diabetes and Endocrinology at Queen Charlottes Hospital and St. Thomas Hospital, London, UK.
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The Limping Child: An Approach to Diagnosis and Management

Angela Cox, MB BS, FRACP; Roger Allen, MB BS, FRACP
T
1
he child with a limp is a common problem with broad differential diagnoses, of which few are true emergencies. This review focuses on the clinical evaluation of children presenting with a limp, including key elements of the history and examination and ap-
propriate diagnostic tests and management. It also focuses on the more common and important causes of limp in children. A limp is defined as a deviation from the normal gait pattern expected for a childs age. It is a common complaint in childhood and was reported to account for four in
every 100 visits to one paediatric emergency department in the USA.2 The conditions to consider in the differential diagnosis will depend in part on the patients age. Common conditions leading to a limping child include soft tissue or bone injuries; infection of the bone, soft tissues or joints; and neuromuscular, congenital, developmental, ischaemic and neoplastic processes. A prospective study that evaluated 243 children younger than 14 years of age who presented to a paediatric emergency department with limp and no history of trauma showed that 3: the median age of affected children was 4 years limp was more common in boys (2:1) limp was painful in 80% of cases, and pain was localized to the hip in 34% and the knee in 19% of cases transient synovitis or irritable hip was the most common cause of limp, accounting for 40% of all cases. Although the majority of affected children will have benign, self-limiting causes for limp, a significant proportion of children will require additional diagnostic studies and subspecialty care to diagnose and manage more serious underlying conditions.
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Important aspects of the history of a limping child
disorders and is less likely to present acutely. Pain that is worse in the morning and associated with stiffness is suggestive of an inflammatory process, whereas pain that is worse at the end of the day is
Age Onset of pain and limp: sudden or insidious, time of day Any history of trauma, including non-accidental injury Association with pain and its location, including referred pain Preceding viral illness, which can precede transient synovitis Aggravating factors Functional limitations Constitutional symptoms, such as fever, weight loss or malaise
Three major factors will cause a child to limp pain, weakness, or
Clinical examination of a limping child
mechanical or structural abnormalities
Carry out a general examination, including temperature and skin rashes Observe the childs gait and posture, looking for pelvic tilting or asymmetry Test muscle strength with a squat, Trendelenburg test, and heel and toe walk Inspect extremities, looking for erythema, swelling or rashes Palpate bones and joints, noting any tenderness, masses, effusion or warmth Observe passive and active range of motion in the spine and lower extremities Measure leg length and calf and thigh circumferences Carry out a neurological examination, checking sensation and reflexes
more likely to be mechanical in nature. Patients or their parents should be asked about the presence of constitutional symptoms. Fever and chills may suggest an infectious process such as osteomyelitis or septic arthritis. Patients with juvenile arthritis or malignancy may present with fever and loss of weight.
CLINICAL EXAMINATION
The clinical examination should begin by observing
HISTORY
History taking in children can be a challenge, especially in children who are unable to talk or adequately localize the site of pain (see the box on this page). The parents should be asked what their concerns are and what problems they have noticed. The age of the child is important because different diagnoses are entertained dependent on the childs age. Is the limp associated with pain? Painless limp is often the result of mechanical or neuromuscular
the childs gait pattern or posture if able. Three major factors will cause a child to limp pain, weakness, or mechanical or structural abnormalities. Any asymmetry of the legs, rotation of a foot or other compensatory postures should be noted (see the box on this page). A general examination is also important to evaluate for signs of systemic disease or rule out causes of referred pain. A more focused examination of the lower extremities should then be performed. Any erythema, rashes, swelling or other deformities should be noted, and the bones and joints should be palpated
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to identify areas of tenderness, masses, effusion or warmth. All lower extremity joints, that is, hips, knees and ankles, should be examined for range of movement; the spine should also be included in this examination. This will help in the identification of any painful or stiff joints or any muscle weakness. A neurological examination including sensation, tone and power reflexes should also be performed because many neuromuscular problems can present with limp.
Investigations of a limping child
INVESTIGATIONS
After a thorough history and clinical examination have been conducted, potential differential diagnoses should be identified. Further investigations can then help to make the diagnosis (see the box on this page). A full blood count and measurement of C-reactive protein levels and erythrocyte sedimentation rate should be considered in the assessment of the limping child. If an effusion is present and infection is suspected, then a joint aspiration should be performed. If the joint is septic, white cell counts will usually be greater than 50,000 cells/mm3 and will be predominantly neutrophils. Imaging may also be useful in determining a diagnosis. Plain X-ray is usually of low yield but can be useful in identifying slipped upper femoral epiphyses or Perthes disease. Ultrasound is useful for assessing joint effusion in hips or localizing a collection, for example, an abscess. A bone scan is very sensitive but not highly specific. It will highlight areas of increased or decreased metabolic activity, which may be due to infection, inflammation, trauma, neoplasm or avascular disease.
Full blood count, including a differential white cell count Erythrocyte sedimentation rate: can be elevated in infective inflammatory or malignant conditions C-reactive protein: more sensitive for early infection or inflammation Joint aspiration, if effusion present: followed by a full blood count and differential white cell count, Gram stain, and culture Blood cultures: for causative organism in osteomyelitis or septic arthritis Imaging: plain X-ray, ultrasound, bone scan, magnetic resonance imaging or computed tomography Surgical: arthroscopy
Common causes of limp in children
Aged 1 to 5 years
Trauma Transient synovitis Osteomyelitis and/or septic arthritis Discitis Juvenile idiopathic arthritis Malignancy
Aged 5 to 10 years
Trauma Transient synovitis Osteomyelitis and/or septic arthritis Perthes disease Juvenile idiopathic arthritis Malignancy
Aged 10 to 15 years
Trauma Septic arthritis Slipped upper femoral epiphyses Juvenile idiopathic arthritis Malignancy
CAUSES OF LIMPING
The common causes of limp in children are listed in the box on this page.
Transient Synovitis Transient synovitis or irritable hip is the most common cause of limp in preschool-aged children. It can
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Begin the clinical examination by observing the child's gait pattern or posture.
evated. An ultrasound, if performed, should show a small effusion. Transient synovitis is a self-limited inflammatory condition that usually resolves within 7 to 10 days. Treatment is rest and analgesia, usually with a non-steroidal anti-inflammatory drug (NSAID) such as ibuprofen or naproxen, based on the severity of the symptoms.
Transient synovitis or irritable hip is the most common cause of limp in preschool-aged children
occur between 18 months and 12 years of age and is a diagnosis of exclusion. The typical presentation is of a preschool-aged child, who is otherwise well, limping or refusing to walk, and it is often preceded by a mild viral infection. The child will be mostly afebrile or have a lowgrade fever with a mild to moderate decrease in range of movement in the affected hip. Inflammatory markers are usually normal or only slightly elJPOG MAY/JUN 2012 120
Septic Arthritis and Osteomyelitis Differentiating transient synovitis from septic arthritis can be difficult because both conditions can present with a decreased range of movement in the hip. The presence of raised inflammatory markers, fever and a history of non-weight-bearing makes septic arthritis the most likely diagnosis. If a septic process is suspected, the joint should be aspirated and the fluid sent for cell count, Gram stain, and culture and sensitivities. There is overlap between synovial cell counts in infection and inflammatory
PAEDIATRICS
conditions, but if the white blood cell count is more than 50,000 cells/mm3 and predominantly neutrophils, infection should be presumed. Treatment of patients with septic arthritis is surgical drainage and use of antibiotics (usually flucloxacillin) to cover infection with Staphylococcus aureus. The presentation of osteomyelitis overlaps with that of septic arthritis, and treatment is similar with empirical antibiotic therapy, usually with flucloxacillin. Open surgical drainage and washout may be required if there is evidence of joint involvement or abscess. Discitis, infection of the disc space, can also present with limp and should be suspected in younger children who are refusing to walk and cry when picked up. They may be tender in the region of the affected disc, usually L1 to L5.
Figure 1. Perthes disease in a 4-year-old boy. Note the flattening of the left femoral head and sclerosis.
Perthes Disease Perthes disease is an avascular necrosis of the femoral head and is seen commonly between the ages of 4 and 9 years and more often occurs in boys (Figure 1). The onset is often insidious with a painless limp and then the development of hip, groin, lateral thigh or knee pain. On examination, the patient may have a leg length discrepancy with decreased abduction and internal rotation of the hip. X-ray changes vary depending on the stage of the disease, but there is usually flattening and fragmenting of the femoral head. A bone scan may pick up earlier changes. Treatment of patients with Perthes disease may vary from close observation to bracing or surgery with the goal being to maintain range of movement and containment of the femoral head within the acetabulum. Slipped Upper Femoral Epiphysis Slipped upper femoral epiphysis is a fracture of the growth plate leading to slippage of the femoral epiphyses off the femoral neck (Figure 2). It more commonly affects teenage boys, particularly those who
Figure 2. Slipped upper femoral epiphysis in the left hip of a 9-year-old girl.
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Osteosarcomas are the most common type of bone tumour seen in children.
rotated and shortened. Surgical treatment is often needed with fixation of the femoral epiphyses by pinning.
There is no one diagnostic test for juvenile idiopathic arthritis, and the diagnosis is made on clinical grounds and by excluding other conditions
are overweight and skeletally immature. There is also an association with hypothyroidism. The presentation can be acute or chronic with a limp and often pain referred to the knee or thigh. On examination, the leg may be externally
Juvenile Idiopathic Arthritis Juvenile idiopathic arthritis is the most common chronic paediatric rheumatological disease. It is an inflammatory arthritis that affects one or more joints and presents in children younger than 16 years of age. Symptoms can last for more than 6 weeks, and the condition is classified on the basis of disease pattern over the first 6 months. On initial presentation, particularly in patients with the oligoarticular subtype of the disease, monoarticular swelling can be present. This is more likely to involve the knee or ankle, and isolated hip arthritis is an uncommon presentation of juvenile idiopathic arthritis. During history taking, it is important to ask about early morning stiffness or any fevers, rashes and other systemic features. Examination should include examination of all joints including asymptomatic ones and checking for com-
PAEDIATRICS
plications of disease, for example, leg length discrepancy, muscle wasting or growth failure. There is no one diagnostic test for juvenile idiopathic arthritis, and the diagnosis is made on clinical grounds and by excluding other conditions. Most, but not all, patients will have raised inflammatory markers and some will have associated anaemia and/or thrombocytosis. Depending on the severity of the condition, patients can be treated with a range of medications from NSAIDs, oral and intra-articular corticosteroids to disease-modifying anti-rheumatic drugs such as methotrexate and the new biologic therapies, such as the tumor necrosis factor antagonists etanercept and adalimumab.
MALIGNANCY
Neoplasms are some of the most concerning causes of limp or limb pain in children. Children may have pain or limp caused by a tumour, for example, osteosarcoma, non-specific pain from leukaemia or gait deterioration from a tumour of the central nervous system. Pain from leukaemia is often out of proportion to the findings on examination. There may also be pallor, lymphadenopathy and hepatosplenomegaly, and the white cell count is usually abnormally high or low with abnormal cells, lymphoblasts, seen on film. A bone marrow aspirate will confirm the diagnosis. Osteosarcomas are the most common type of bone tumour seen in children and commonly present in older children in the distal femur or proximal tibia. The pain will often be reported as being worse at night, and a radiolucent defect will be visible on X-ray. Benign bone tumours can also present with pain that is worse at night. Osteoid osteomas are benign tumours of bone that characteristically respond very well to NSAIDs and usually have typical X-ray findings of a radiolucent nidus surrounded by sclerotic bone and are hot on bone scan.
The causes of limp in children are diverse, from benign selfresolving to serious underlying conditions.
WHO TO REFER
Specialist referral is required for children with: suspected slipped upper femoral epiphyses suspected Perthes disease suspected bone or joint infection suspected juvenile idiopathic arthritis any persistent musculoskeletal symptom.
CONCLUSION
The limping child is a common clinical presentation in the primary health-care setting. The causes are
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Key points
FURTHER READING
Abbassian A. The limping child: a clinical approach to diagnosis. Br J Hosp Med (Lon) 2007;68:246250. Cassidy, JT, Petty, RE. Textbook of Pediatric Rheumatology. 5th Ed. Philadelphia: WB Saunders; 2005. Lawrence LL. The limping child. Emerg Med Clin North Am 1998;16:911929, viii. MacEwen GD, Dehne R. The limping child. Pediatr Rev 1991;12:268 274.
History, examination and simple laboratory tests can identify most serious causes of limp in children. The presence of acute pain, raised inflammatory markers, fever and non-weight-bearing makes septic arthritis the most likely diagnosis. It is important to remember that muscle weakness and malignancy can be causes of limp. Referred pain may be present, and the pathology may not be at the site of the pain.
2011 Medicine Today Pty Ltd. Initially published in Medicine Today September 2011;12(9):3136. Reprinted with permission.
diverse, from benign self-resolving conditions to infections, malignancy, and inflammatory disorders. Many conditions causing limp can be managed by the primary care physician. Immediate referral should be made if septic arthritis is suspected, and advice should be sought for any musculoskeletal complaint that is persistent or worrisome.
About the Authors

Dr Cox is a Paediatric Rheumatologist at Monash Childrens Hospital, Melbourne. Declaration of interest: None. Dr Allen is a Paediatric Rheumatologist at The Royal Childrens Hospital, Melbourne, Victoria, Australia. Declaration of interest: Dr Allen has been on paediatric advisory committees for Novartis and Roche and has been a principal or associate investigator in various drug trials sponsored by Merck, Amgen, Wyeth and Roche.
References
1. Thompson GH. Bone and joint disorders. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th ed. Philadelphia: WB Saunders; 2004:22512252. 2. Singer JI. The cause of gait disturbance in 425 pediatric patients. Pediatr Emerg Care 1985;1:710. 3. Fischer SU, Beattie TF. The limping child: epidemiology, assessment and outcome. J Bone Joint Surg Br 1999;81:10291034.
HKCOG GuidelinesPrediction of High-risk Pregnancies

The Hong Kong College of Obstetricians and Gynaecologists
INTRODUCTION
The objective of this guideline is to examine scientific evidence about capacities to predict high-risk obstetric problems. Frontline clinicians may exercise their clinical judgement about risk-benefit appraisal in relation to individual needs and available support of the patient as well as capacity of the service provider. This guideline would serve as an updated reference to summarize the current evidence on various risk assessment methods for high-risk pregnancies, focusing on how accurate they are together with their limitations. The information might be useful for triaging the management of pregnancies such as: appropriate and timely referrals of high-risk centres shared care between Maternal and Child Health Centres and hospitalbased obstetrics units midwifery vs obstetrician-led antenatal care and deliveries determining the frequency of anassessment. This guideline is going to focus on four common types of high-risk pregnancies: pre-eclampsia; preterm deliveries; gestational diabetes mellitus (GDM); and major placenta praevia and accreta. Twin or higher-order multiple pregnancies are not included as they are alGuidelines No. 11, Part I and II). 1,2 Screening for fetal aneuploidies and fetal structural abnormalities, to which there are Pre-eclampsia, which affects 2% of pregnancies, is a major cause of maternal and
High-risk pregnancies are difficult to predict and prevent.
pregnancies
to
tertiary
already good evidence-based guidelines, 3 are also outside the scope of this guideline.
PREDICTION OF PREtenatal clinic visits based on risk ready high-risk to start with (HKCOG ECLAMPSIA
perinatal morbidity and mortality.46
prophylactic use of aspirin that this may reduce the incidence of pre-eclampsia by about 50%, provided treatment is initiated before 16 weeks. 8 The approach to screening recommended by NCCWCH, which essentially treats each of the risk factors as a separate screening test, would falsely classify two-thirds of the obstetric population as being at high risk and in need of intensive monitoring.9 An alternative approach is to combine the maternal characteristics and previous history into an algorithm derived
events leading from impaired placentation to development of clinical symptoms of pre-eclampsia.
Maternal Factors The National Collaborating Centre for Womens and Childrens Health (NCCWCH) in UK has issued guidelines on routine prenatal care recommending that at the first visit, a womans level of risk for pre-eclampsia should be evaluated by a series of maternal characteristics, such as maternal
The degree of impaired placentation and the incidence of adverse fetal and maternal short-term and long-term consequences of pre-eclampsia are inversely related to the gestational age at onset of the disease
by multivariate analysis to estimate the individual patient-specific risk for pre-eclampsia, and with such an approach about one-third of pregnancies developing preeclampsia would be detected at a falsepositive rate (FPR) of 10%.9
age, body mass index, and previous and family history of pre-eclampsia, so that a plan for her schedule of prenatal visits can be formulated. 7 The aim of such early identification of women at high risk is to allow intensive maternal and fetal monitoring, leading to an earlier diagnosis of pre-eclampsia with the potential for preventing an adverse outcome. Additionally, there is evidence from randomized studies on the
Biophysical and Biochemical Markers The performance of screening can be improved by combining history with a series of biophysical and biochemical markers which are altered from as early as the first trimester of pregnancy in cases that subsequently develop pre-eclampsia. In the pre-eclampsia group, compared with unaffected controls, at 1113 weeks uterine artery pulsatility index and mean arterial pressure, and maternal serum or plasma levels of soluble endoglin, inhibin A, activin A, pentraxin 3 and P-selectin are increased, whereas serum pregnancyassociated plasma protein A, placental growth factor and placental protein 13 are decreased. 1023 These biophysical and biochemical markers are thought to be involved in placentation or in the cascade of
Early, Intermediate and Late Preeclampsia There is evolving evidence that both the degree of impaired placentation and the incidence of adverse fetal and maternal short-term and long-term consequences of pre-eclampsia are inversely related to the gestational age at onset of the disease.2429 Consequently, the end point in screening for pre-eclampsia by first-trimester biophysical and biochemical markers should not be total pre-eclampsia, but the condition should be subdivided according to gestational age at delivery. This subdivision has so far been limited to early pre-eclampsia, requiring delivery before 34 weeks and late pre-eclampsia. Akolekar et al 30 recently showed that there are now sufficient data to allow further subdivision of the cases delivering at or after 34 weeks into intermediate pre-eclampsia and late pre-eclampsia groups, delivering at 3437 weeks and after 37 weeks, respectively. Screening of Pre-eclampsia Proposed by Fetal Medicine Foundation This prospective screening study 30 in a UK heterogeneous population of about 35,000 singleton pregnancies has found that the prevalence of early, intermediate and late pre-eclampsia is 0.3%, 0.6% and 1.3%, respectively. Logistic regression analysis was used to derive the a priori risk for each of the pre-eclampsia
There are marked differences in the prevalence of gestational diabetes mellitus in different ethnic groups.
groups from maternal characteristics. The risk for pre-eclampsia increased with maternal weight and decreased with height; it was higher in women of African and South Asian racial origin than in Caucasians, and increased in women conceiving after the use of ovulation induction drugs, in those with a personal or family history of pre-eclampsia, and in those with preexisting chronic hypertension or diabetes mellitus. In parous women with no previous pre-eclampsia, the risk of developing pre-eclampsia in the current pregnancy was reduced by 6070%. In general, the odds ratios for the factors in maternal history which defined the a priori risk for pre-eclampsia were inversely proportional to the gestation at delivery, with
higher ratios for early disease compared with those in intermediate and late preeclampsia. Algorithms that combine the various maternal characteristics at 1113 weeks could potentially identify 33%, 28% and 25% of pregnancies that subsequently develop early, intermediate and late pre-eclampsia, respectively, at a FPR of 5%. The algorithm is freely accessible at the Fetal Medicine Foundation website www.fetalmedicine.com. The patient-specific a posteriori risk for early, intermediate and late pre-eclampsia were calculated by multiplying the a priori patient characteristics-derived risk with the likelihood ratio of a series of biophysical and biochemical markers after appropriate adjustments for the intercorrelations between these mark-
ers. As in the case of maternal factors, the differences in biophysical and biochemical markers of impaired placentation between the pre-eclampsia and unaffected groups were, in general, more pronounced in those developing early disease compared with those in intermediate or late pre-eclampsia. Algorithms which combine maternal characteristics and biophysical and biochemical tests at 1113 weeks could potentially identify about 90%, 80% and 60% of pregnancies that subsequently develop early, intermediate and late preeclampsia, respectively, at a FPR of 5%. Early estimation of patient-specific risks for these pregnancy complications would improve pregnancy outcome by shifting prenatal care from a series of routine visJPOG MAY/JUN 2012 127
its to a more individualized patient- and disease-specific approach both in terms of the schedule and content of such visits. In the case of pre-eclampsia, effective early identification of the high-risk group could potentially improve the outcome by directing such patients to specialist clinics for close surveillance and would be the basis for future studies investigating the potential role of pharmacological interventions, such as aspirin, starting from the first trimester to improve placentation and reduce the prevalence of the disease.
of spontaneous preterm delivery before 34 weeks in the following discussion. The pathophysiologic events that trigger spontaneous preterm birth are largely unknown but include decidual hemorrhage (abruption), mechanical factors (uterine overdistention or cervical incompetence), and hormonal changes (perhaps mediated by fetal or maternal stress). In addition, several cervicovaginal infections have been associated with preterm labour.32
Local Situation The comprehensive assessment at 1113 weeks promoted by the Fetal Medicine Foundation is not ready to be implemented in Hong Kong. Furthermore, even if we can offer this comprehensive assessment at 1113 weeks, the efficacy and safety of this new antenatal care model in local pregnant women still require a prospective demonstration trial before clinical use.
PREDICTION OF PRETERM DELIVERIES

Preterm birth is the leading cause of perinatal death and handicap in children, and the vast majority of mortality and morbidity relate to early delivery before 34 weeks which occurs in about 2% of singleton pregnancies. In two-thirds of the cases, this is due to spontaneous onset of labour or preterm pre-labour rupture of membranes, and in the other one-third, it is iatrogenic owing to pre-eclampsia.31 We will focus on the risk assessment
Clinical History Previous spontaneous preterm birth, second-trimester miscarriage, advanced maternal age, smoking, previous cervical surgery (large loop excision of the transformation zone, or cone biopsy) and multiple pregnancies are the risk factors for spontaneous preterm delivery. Therefore, traditional method of antenatal screening for spontaneous early preterm delivery is based on the abovementioned maternal characteristics, such as age, race and smoking status, and obstetric history. Risk-scoring systems, which attempt to define women as being at high or low risk according to these maternal factors, have been shown to have a low detection rate and a high FPR. Moreover, it is much less discriminating for primigravid than multigravid patients. Data extracted from a recent systematic review of the literature demonstrated that with the most commonly used risk scoring system, 33 the detection rate of spontaneous delivery before 37 weeks was 38% for a FPR of 17%. 34
Sonographic Cervical Length at 20 24 Weeks The risk of spontaneous preterm birth is inversely related to cervical length measured by transvaginal sonography at 20 to 24 weeks.3539 A cervical length of 25 mm or less had a sensitivity, specificity, positive predictive value, and negative predictive value of 76%, 68%, 20%, and 96%, respectively, to identify preterm singleton birth at less than 34 weeks of gestation.40 The detection rate of screening for preterm delivery before 32 weeks at a fixed FPR of 10% was 38% for maternal factors, 55% for cervical length, and 69% for combined testing. The detection rate of screening by a combination of maternal factors and the measurement of cervical length was substantially higher than that of screening by each method alone.38 According to a recent systematic review and meta-analysis,41 a cervical length 20 mm at 2024 weeks was the most accurate in predicting preterm birth < 32 and < 34 weeks in asymptomatic women with twin pregnancy. The pooled sensitivities, specificities, and positive and negative likelihood ratios were 39% and 29%, 96% and 97%, 10.1 and 9.0, and 0.64 and 0.74, respectively. Biochemical Markers A growing body of evidence indicates that a positive fetal fibronectin test between 2436 weeks in cervical and/or vaginal fluids is associated with preterm delivery in the next 7 days both in patients with threatened preterm labour and in symptomatic patients, with a positive predictive value of 1330%. However, its clinical
usefulness may rest primarily with its high negative predictive value (99%).42 On the other hand, there are no other useful biophysical (such as uterine artery Doppler) or biochemical markers (such as maternal serum concentrations of pregnancy-associated plasma protein A, free -human chorionic gonadotrophin, placental growth factor, placental protein 13, disintegrin and metalloproteinase domain-containing protein 12, inhibin A, and activin A) of spontaneous early delivery.43
Future Directions The patient-specific risk for spontaneous delivery before 34 weeks might be determined by an algorithm combining maternal characteristics and obstetric history at 1113 weeks. 43 There is some evidence that sonographic measurement of endocervical length at 11 to 13 weeks is inversely related to the likelihood for subsequent spontaneous early delivery. 44 Therefore, this a priori risk might be further modified by sonographic measurement of cervical length as early as 11 to 13 weeks gestation.31 Further studies are also required to investigate whether a combination of biophysical (cervical length) and biochemical (fetal fibronectin) markers may better identify patients at risk for preterm delivery.45
Major placenta praevia and accreta can be predicted by an ultrasound assessment at 20 weeks with reasonable accuracy.
cy. 46 It is common in Hong Kong, with prevalence reported to be 14.2% based on the World Health Organization (WHO) 1998 diagnostic criteria.
47
reduce the complications.5052 In addition, pregnant women with GDM are also at increased risk for developing type 2 diabetes mellitus in the future. 53 The diagnosis can increase the awareness among these patients to institute measures to reduce the development of type 2 diabetes mellitus, such as postnatal screening and modification of lifestyle.54
In the past, GDM
was divided into a less severe degree of glucose impairment, namely impaired glucose tolerance (IGT), and the more severe form of GDM. This definition was changed in the WHO 1998 report when GDM included both gestational IGT and the previous GDM. Pregnant women who meet the WHO criteria for diabetes mellitus or IGT are both classified as having GDM. This is a reflection of the continuous relationship between maternal glycaemia and macrosomia-related perinatal risks without a biological threshold.48,49 GDM has been associated with multiple perinatal complications,50 including macrosomia (21%), shoulder dystocia (3%), brachial plexus injury (0.6%), and neonatal hypoglycaemia (6.6%). Treatment of even mild degree of GDM has been shown to
PREDICTION OF GDM
Gestational diabetes mellitus is defined as carbohydrate intolerance resulting in hyperglycaemia of variable severity with onset or first recognition during pregnan-
Risk Factor-based vs Universal Screening GDM is largely asymptomatic, unless there is maternal glycosuria or fetal complications such as large for gestational age or polyhydramnios. There are two approaches to achieving diagnosis: risk factor-based screening and universal screening.55 Studies have identified several risk factors including older maternal age, high body mass index, previous birth of a large baby, a family history of diabetes mellitus, excessive weight gain, and cigarette
Table. Risk of placenta praevia (PP) and ultrasonographic (USG) findings of low-lying placenta at 1823 weeks of gestation
No. of patients
Gestational age (wk)
Type of USG/ distance of placenta overlapping cervical os

Transvaginal > 0 mma > 15 mm > 25 mm Transvaginal > 0 mma > 25 mm Transabdominal / overlapping cervical os
Incidence at USG
Positive predictive value for final PP
Overall incidence of PP
Taipale et al65 (Finland)
3,696
1823
1.5% 0.68% 0.27% 0.48% 0.14% 3.75%
8.8% 18.5% 40% 67% 100% 22.7%
0.14% 0.14% 0.11% 0.32% 0.14% 1.1%
Becker et al66 (Germany) Fung et al67 (Hong Kong)
8,650
2023
16,236
Second trimester (mainly 20 weeks)
Placenta reaching cervical os.
smoking.56 In addition, there are marked differences in the prevalence of GDM in different ethnic groups, with South East Asians consistently shown to be of higher risk.
57
Outcome (HAPO) study, 49 the International Association of Diabetes and Pregnancy Study Groups (IADPSG) published a new set of screening algorithm, trying to offer a standardized platform for the diagnosis. It encompasses the use of fasting,
60
In the last decade, there have been promising results from the use of biomarkers in the first trimester, combined with maternal characteristics, to predict the development of GDM in the latter part of gestation.62 More prospective, large-scale studies are required to verify the results before clinical use.
Because of this, the guideline by
Hong Kong College of Obstetricians and Gynaecologists on GDM suggests universal screening based on ethnicity for Hong Kong Chinese pregnant women.
58
1-hour and 2-hour 75 g OGTT with any one value above the threshold (5.1, 10.0 and 8.5 mmol/L, respectively) indicating a diagnosis. Random or fasting glucose is per-
PREDICTION OF MAJOR Screening and Diagnostic Tests formed at the first prenatal visit to diag- PLACENTA PRAEVIA AND Various screening algorithms have been nose overt diabetes as early as possible. ACCRETA
suggested by different professional bodies throughout the world. There are dif59
OGTT is performed in the second trimester (24 to 28 weeks). The American Diabetes Association has adopted this algorithm in the autumn of 2010.61 It is anticipated that more studies will be performed to investigate if this translates to improved clinical outcome for both pregnant women and their offspring. The Royal College of Obstetricians and Gynaecologists and the National Institute for Health and Clinical Excellence support placental localization in routine ultrasound scanning at around 20 weeks of gestation.63 Transvaginal scan is safe and should
ferences in the gestational age to perform the screening, the screening methods (random glucose or direct oral glucose tolerance test (OGTT) 75 g or 100 g), and the cut-offs used. On the basis of the Hyperglycemia and Adverse Pregnancy
be used to improve the accuracy of the diagnosis of low-lying placenta at 20 weeks of gestation.64 The Table presents ultrasound findings in predicting the risk of placenta praevia. Significant migration to allow vaginal delivery is unlikely if the placenta substantially overlaps the internal os by over 25 mm at 2023 weeks of gestation.
suspected to have placenta accreta. Visualization of lacunae had the highest sensitivity of 79% with positive predicative value of 93%.70
Therefore, no single test would be able to predict this group of high-risk pregnancies with heterogeneous aetiology. A new set of screening algorithm for GDM has been proposed by IADPSG, but it should be noted that the screening would not be completed by 28 weeks. Major placenta praevia and accreta are probably the only high-risk obstetric conditions (out of the four described in this guideline) which can be predicted by an ultrasound assessment at 20 weeks with reasonable accuracy, especially with history of previous caesarean section. Future research to further improve the performance of various algorithms to predict high-risk pregnancies, especially in early gestation, is necessary before the traditional standard regular antenatal care could be replaced.
2012 The Hong Kong College of Obstetricians and Gynaecologists. Initially published as Guidelines on Prediction of High-risk Pregnancies, Number 15, September 2011. Reprinted with permission.
Time of Follow-up Scan Women who bleed should be managed individually according to their needs. In cases of asymptomatic women with suspected minor praevia, follow-up imaging can be left until 36 weeks of gestation. In cases with suspected asymptomatic major placenta praevia or a question of placenta accreta, imaging should be performed at around 32 weeks of gestation to clarify the diagnosis and allow planning for thirdtrimester management, further imaging, and delivery. 63 Risk of Placenta Accreta Incidence of placenta accreta in patients with placenta praevia increased with the number of previous caesarean sections: 1.9%, 15.6%, 23.5%, 29.4%, 33.3%, and 50.0% after zero, one, two, three, four, and five previous caesarean sections, respectively. 68 Women with both anterior or central placenta praevia and two or more previous caesarean deliveries have a 40% risk of placenta accreta.69 In those patients with previous caesarean section and anterior/ central placenta praevia, one should look out for placenta accreta. Between 15 to 20 weeks, about 1.6% of the patients will be
Recommendation Ultrasound at 20 weeks (with the help of transvaginal scan) to detect the placenta site is recommended. If the placenta overlaps the internal os by more than 25 mm, the risk of placenta praevia is 40% to 100%. Follow-up ultrasound scan at 32 weeks is necessary to confirm the diagnosis. Patients with anterior and low-lying placenta and previous caesarean section should have an ultrasound scan to look for placenta accreta. If major placenta praevia or placenta accreta is suspected, inpatient management should be offered after 34 weeks of pregnancy. Even if there are no symptoms before, there is a small risk that the patient can bleed suddenly and severely, which may warrant an urgent caesarean section. If there is low-lying placenta after 20 weeks without bleeding, the patient may be able to have care at home. However, she should be able to get to the hospital quickly and easily at any time.71
Acknowledgements
This document was prepared by Dr Leung Wing Cheong, Dr Lau Wai Lam, Dr Chan Lin Wai Daniel, Dr Fung Tak Yuen, Dr Lau Tze Kin, Professor Leung Tak Yeung, Dr Lee Chin Peng, Dr Leung Kwok Ling Ares and Professor Ngan Yuen Sheung Hextan and was endorsed by the Council of the Hong Kong College of Obstetricians and Gynaecologists. This guideline was produced by the Hong Kong College of Obstetricians and Gynaecologists as an educational aid and reference for obstetricians and gynaecologists practicing in Hong Kong. The guideline does not define a standard of care, nor is it intended to dictate an exclusive course of management. It presents recognized clinical methods and techniques for consideration by practitioners for incorporation into their practice. It is acknowledged that clinical management may vary and must always be responsive to the need of individual patients, resources, and limitations unique to the institution or type of practice. Particular attention is drawn to areas of clinical uncertainty where further research may be indicated.
CONCLUSION
Many high-risk pregnancies, such as preeclampsia and preterm deliveries, that we deal with in clinical practice are not discrete entities but are syndromes with more than one cause. It thus explains the disappointing results when we tried to predict and prevent high-risk pregnancies.
References
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Hypertens Pregnancy 2003;22:143148. 27. Moldenhauer JS, Stanek J, Warshak C, Khoury J, Sibai B. The frequency and severity of placental findings in women with pre-eclampsia are gestational age dependent. Am J Obstet Gynecol 2003;189:11731177. 28. Egbor M, Ansari T, Morris N, Green CJ, Sibbons PD. Morphometric placental villous and vascular abnormalities in early- and late-onset preeclampsia with and without fetal growth restriction. BJOG 2006;113:580589. 29. Yu CK, Khouri O, Onwudiwe N, Spiliopoulos Y, Nicolaides KH; Fetal Medicine Foundation Second-Trimester Screening Group. Prediction of preeclampsia by uterine artery Doppler imaging: relationship to gestational age at delivery and small-for-gestational age. Ultrasound Obstet Gynecol 2008;31:310313. 30. Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH. Prediction of early, intermediate, and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 1113 weeks. Prenat Diagn 2011;31:6674. 31. Nicolaides KH. A model for a new pyramid of prenatal care based on the 11 to 13 weeks assessment Prenat Diagn 2011;31:36. 32. Di Renzo GC, Roura LC; European Association of Perinatal Medicine-Study Group on Preterm Birth. Guidelines for the management of spontaneous preterm labor. J Perinat Med 2006;34:359366. 33. Creasy RK, Gummer BA, Liggins GC. System for predicting spontaneous preterm birth. Obstet Gynecol 1980;55:692695. 34. Honest H, Bachmann LM, Sundaram R, Gupta JK, Kleijnen J, Khan KS. The accuracy of risk scores in predicting preterm birtha systematic review. J Obstet Gynaecol 2004;24:343359. 35. Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network. N Engl J Med 1996;334:567572. 36. Heath VC, Southall TR, Souka AP, Elisseou A, Nicolaides KH. Cervical length at 23 weeks of gestation: prediction of spontaneous preterm delivery. Ultrasound Obstet Gynecol 1998;12:312317. 37. Kagan K, To M, Tsoi E, Nicolaides K. Preterm birth: the value of sonographic measurement of cervical length. BJOG 2006;113:5256. 38. To MS, Skentou CA, Royston P, Yu CK, Nicolaides KH. Prediction of patient-specific risk of early preterm delivery using maternal history and sonographic measurement of cervical length: a population-based prospective study. Ultrasound Obstet Gynecol 2006;27:362367. 39. Celik E, To M, Gajewska K, Smith GC, Nicolaides KH; Fetal Medicine Foundation Second Trimester Screening Group. Cervical length and obstetric history predict spontaneous preterm birth: development and validation of a model to provide individualized risk assessment. Ultrasound Obstet Gynecol 2008;31:549554. 40. Mella MT, Berghella V. Prediction of preterm birth: cervical sonography. Semin Perinatol 2009;33:317324. 41. Conde-Agudelo A, Romero R, Hassan SS, Yeo L. Transvaginal sonographic cervical length for the prediction of spontaneous preterm birth in twin pregnancies: a systematic review and meta-analysis. AJOG 2010;203:128.e1e12. 42. Di Renzo GC, Roura LC, Facchinetti F, et al. Guidelines for the management of spontaneous preterm labor: identification of spontaneous preterm labor, diagnosis of preterm premature rupture of membranes, and preventive tools for preterm birth. J Matern Fetal Neonatal Med 2011;24:659667. 43. Beta J, Akolekar R, Ventura W, Syngelaki A, Nicolaides KH. Prediction of spontaneous preterm delivery from maternal factors, obstetric history and placental perfusion and function at 1113 weeks. Prenat Diagn 2011;31:7583. 44. Greco E, Lange A, Ushakov F, Rodriguez Calvo J, Nicolaides KH. Prediction of spontaneous preterm delivery from endocervical length at 11 to 13 weeks. Prenat Diagn 2011;31:8489. 45. Bolt LA, Chandiramani M, De Greeff A, Seed PT, Kurtzman J, Shennan AH. 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A full list of references is available on request to the editorial office.
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Nausea, Vomiting and Hyperemesis Gravidarum

Table 2. Management of hyperemesis gravidarum

ies are present.