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JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY
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PAEDIATRICS
Paediatric Psoriasis Managing Headache in Children

GYNAECOLOGY
Dysmenorrhoea What Are the Benefits and Risks of HRT?

CME ARTICLE
Gestational Diabetes
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J UL/ AUG 2 0 1 2 Vol. 38 No. 4
Journal Watch
133 Proton pump inhibitors and hip fracture in postmenopausal women Screening for cervical cancer in Europe: Cost-effectiveness of HPV versus cytology screening Screening and cervical cancer mortality Nicotine replacement patches in pregnancy: Negative study 134 Peer-led parenting intervention for disruptive child behaviour Results of modern paediatric burn care
133
135 Chlorhexidine to the umbilical cord in developing countries Moderate or late preterm birth and health outcomes Paediatricians influence parental febrile behaviour 136 Oral amoxicillin for severe early childhood pneumonia in rural Pakistan
136
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
JPOG JUL/AUG 2012 i
J UL/ AUG 2 0 1 2 Vol. 38 No. 4
Review Article
Paediatrics
137 Paediatric Psoriasis Paediatric psoriasis is a common disorder with significant morbidity. New advances in biologic therapy,
as well as recent reviews assessing classification, have led to a greater understanding of the condition of psoriasis. Presented in this review article is an overview of the presentation of psoriasis as well as an up-to-date review of management options. Vyom Sharma, David Orchard
137
Review Article
Gynaecology
147 Dysmenorrhoea Dysmenorrhoea is a medical condition characterized by severe uterine pain during menstruation
manifesting as cyclical lower abdominal pain. Mainstay treatment is generally supportive providing symptomatic relief, and more directive surgical treatment is reserved for specific secondary causes of dysmenorrhoea or for refractory cases. Therefore, patients with primary dysmenorrhoea may simply need reassurance and simple analgesics, while those with secondary dysmenorrhoea require investigation and treatment of the underlying organic problem. An overview of managing this condition is presented in this article. Shilpa Kolhe, Shilpa Deb
147
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JPOG JUL/AUG 2012 ii
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J UL/ AUG 2 0 1 2 Vol. 38 No. 4
Review Article
Gynaecology
157 What Are the Benefits and Risks of HRT? Opinions concerning the benefits and risks of hormone replacement therapy (HRT) have varied over the
past decade. Maintaining and regularly updating ones knowledge about HRT is paramount so that accurate information can be given to patients. Elizabeth Farrell
157
Review Article
Paediatrics
164 Managing Headache in Children Headache is a common symptom in children. Recurrent or persistent headache is most commonly due to
migraine (with and without aura), tension headache, or chronic daily headache. This article will focus on the clinical management of headache in children including migraine. M A McShane, S J Hughes
Continuing Medical Education
169 Gestational Diabetes
169
Historically, there has been a lot of controversy over most aspects of gestational diabetes mellitus (GDM) as well as the relationship between GDM and type II diabetes mellitus. Recently, several major studies have substantially resolved these areas of controversy. LL Chan, WL Lau, WC Leung
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PPI use by postmenopausal women increas-
GYNAECOLOGY
Proton pump inhibitors and hip fracture in postmenopausal women
es the risk of hip fracture among smokers but not among non-smokers.
Khalili H et al. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ 2012; 344 (Feb. 25): 15 (e372).
Screening for cervical cancer in Europe: Cost-effectiveness of HPV versus cytology screening
Human papillomavirus (HPV) testing for cervical cancer screening is more sensitive but less specific than cytological screening. Cost-effectiveness analyses have given varying results partly because key factors vary between countries. A microsimulation model has been used to compared the costeffectiveness of > 1,500 screening policies in five European scenarios. The model was validated using Dutch data, and costs were derived from studies in the Netherlands. The model showed that HPV testing was usually preferable. Primary cytological It has been suggested that regular use of a proton pump inhibitor (PPI) may increase the risk of hip fracture. Data from the US Nurses Health Study have confirmed the association in postmenopausal women. A total of 79,899 postmenopausal women in the study provided biennial information on PPI use and other risk factors from 2000 to 2008. During follow-up, there were 893 hip fractures. The rate of hip fracture was 2.02 events per 1,000 personyears among PPI users and 1.51 events per 1,000 person-years among non-users. After adjustment for age, women who used a PPI for at least 2 years had a 35% increase in risk, the risk increasing with longer use. Among smokers, the use of PPIs increased the risk of hip fracture by 51%, but there was no significant increase in risk with PPIs in nonsmoking women. There is uncertainty about whether screening for cervical cancer reduces cervical cancer mortality or simply increases the time from diagnosis to death (lead time). A study in Sweden has shown that Smoking in pregnancy can cause miscarriage, plascreening might be preferred when the cost of cytology was low and when HPV was highly prevalent and testing for HPV costly. HPV screening is often preferable to cytological screening in cervical cancer screening programmes in Europe.
De Kok IMCM et al. Primary screening for human papillomavirus compared with cytology screening for cervical cancer in European settings: cost effectiveness analysis based on a Dutch microsimulation model. BMJ 2012; 344 (March 1): 17 (e670).
screening improves prognosis. The study included all 1,230 women who had a diagnosis of invasive cervical cancer between 1999 and 2001 in Sweden. For women aged 2365 years, the cure rate was 92% for cancers detected by smear test screening and 66% for cancers detected because of symptoms, a significant difference. The rate of cure was also significantly higher among women screened at recommended intervals than among women overdue for screening. Smear test screening for cervical cancer increases cure rates, and the effect is independent of lead-time bias.
Andrae B et al. Screening and cervical cancer cure: population based cohort study. BMJ 2012; 344 (March 24): 18 (e900); Arbyn M et al. Effect of screening on deaths from cervical cancer in Sweden. Ibid: 11(e804) (editorial).
Screening and cervical cancer mortality
OBSTETRICS
Nicotine replacement patches in pregnancy: Negative study
JPOG JUL/AUG 2012 133
replacement for smoking cessation during pregnancy. Ibid: 846847 (editorial).
and improved life support systems have meant that the prognosis for burns patients has improved in recent decades. Data from a single modern paedi-
PAEDIATRICS
Peer-led parenting intervention for disruptive child behaviour
Parents in socioeconomically disadvantaged groups may have difficulty obtaining appropriate advice and management for children with disruptive behaviour problems. Researchers in London, England, have shown that a peer-led parenting intervention may be effective. cental abruption, preterm birth, low birth weight, and neonatal morbidity and mortality. Behavioural support for smoking cessation is effective in pregnancy, but the value of nicotine replacement therapy is uncertain. A trial in England has failed to show benefit from nicotine replacement patches in pregnancy. A total of 1,050 women smokers (five or more cigarettes a day) were randomized at seven hospitals to nicotine replacement patches or placebo patches for 8 weeks, beginning at 1224 weeks gestation. All subjects received behavioural cessation support. The rate of abstinence from the quit date until delivery (validated by measurements of exhaled carbon monoxide or salivary cotinine) was 9.4% (nicotine replacement) vs 7.6% (placebo), a non-significant difference. Compliance, however, was poor, with only 7.2% of the replacement group and 2.8% of the placebo group continuing with the patches for more than a month. The rates of adverse pregnancy and birth outcomes were similar in the two groups. The addition of nicotine replacement
Day C et al. Evaluation of a peer led parenting intervention for disruptive behaviour problems in children: community based randomised controlled trial. BMJ 2012; 344 (March 24): 17 (e1107); Stewart-Brown S. Peer led parenting support programmes. Ibid: 10 (e1160) (editorial).
atric burns unit in Texas have correlated burn area and prognosis.
The study included 116 families, mostly from black and ethnic minority groups, and 116 index children with disruptive behavioural problems. Randomization was to intervention or waiting list controls. The intervention consisted of an 8-week peerled parenting programme based on principles of social learning theory and delivered by trained peer facilitators in a manualized group format at schools and childrens centres. Using the parent-reported intensity subscale of the Eyberg child behaviour inventory, improvement in child disruptive behaviour and positive parenting practices was significantly greater in the intervention group compared with the control group. All respondents described their satisfaction with the intervention as a great deal or quite a lot. The drop-out rate was 8.5%. The intervention was successful. Between 1998 and 2008, a total of 952 children were treated for burns involving between 30% and > 90% of total body surface area (TBSA). Mean age was 7.3 years and 66% were boys. Overall, mortality was 13% (3% with 3039% burns rising to 55% with > 90% burns). Multi-organ failure developed in 16% of patients, 6% with 3039% TBSA involvement and 45% with >90% TBSA involved, and 9% developed sepsis (2% to 26%). Mortality increased rapidly with 62% or greater TBSA involvement. It is suggested that children with more than 60% TBSA burns should be transferred immediately to a specialist burns unit.
patches to behavioural cessation support was not beneficial, but compliance was poor.
Coleman T et al. A randomized trial of nicotine-replacement therapy patches in pregnancy. NEJM 2012; 366: 808818; Oncken C. Nicotine
Results of modern paediatric burn care

New drug treatments, new grafting techniques,
Kraft R et al. Burn size and survival probability in paediatric patients in modern burn care: a prospective observational cohort study. Lancet 2012; 379: 10131021; Tompkins RG. Survival of children with burn injuries. Ibid: 983984 (comment).
Peer Reviewed
Journal Watch
Chlorhexidine to the umbilical cord in developing countries

About half of all neonatal deaths around the world are caused by infections, and the umbilicus is regarded as a major point of entry for infective organisms, especially in the rural areas of developing countries where hygiene is often poor. Data from Nepal have suggested that the application of chlorhexidine to the umbilical cord after birth could reduce umbilical infection and neonatal mortality. Now, two studies reported in one issue of the Lancet, one in rural Bangladesh and one in rural Pakistan, have confirmed the benefits of cord cleansing with chlorhexidine.
Neonatal mortality was 22.5 per 1,000 live births (SC), 26.6 per 1,000 (MC), and 28.3 per 1,000 (DC), a significant reduction with SC, but not with MC, compared with DC. The rate of severe cord infection (redness and pus) was 3.3 per 1,000 (SC), 1.2 per 1,000 (MC), and 4.2 per 1,000 (DC), a significant reduction with MC, but not with SC, compared with DC. These researchers conclude that cord cleansing with chlorhexidine is effective, but the optimum frequency of application is to be established. In rural Pakistan, the study included 187 population clusters and 9,741 neonates. Randomization was to one of four options for infants delivered by traditional birth attendants (TBAs): supply of 4% chlorhexidine solution to be applied to the cord by the TBA at birth and then daily by family members for up to 14 days, and supply of soap for handwashing; supply of chlorhexidine only; supply of soap for handwashing only; or promotion of dry cord care. Chlorhexidine cleansing was associated with a significant 42% reduction in risk of omphalitis compared with dry cord care, but handwashing had no significant effect. Similarly, chlorhexidine was associated with a significant 38% reduction in neonatal mortality, but there was no reduction with handwashing. These researchers conclude that cord cleansing with chlorhexidine is effective and that the provision of chlorhexidine in birth kits might reduce neonatal mortality.
El Arifeen S et al. The effect of cord cleansing with chlorhexidine on neonatal mortality in rural Bangladesh: a community-based, clusterrandomised trial. Lancet 2012; 379: 10221028: Soofi S et al. Topical application of chlorhexidine to neonatal umbilical cords for prevention of omphalitis and neonatal mortality in a rural district of Pakistan: a community-based, cluster-randomised trial. Ibid: 10291036; Osrin D, Hill ZE. Chlorhexidine cord cleansing to reduce neonatal mortality. Ibid: 984986 (comment).
representative prospective cohort study including 18,818 infants born in 20002002 and still living in the UK at the age of 9 months. Health outcomes in relation to gestational age at birth were assessed at ages 3 and 5 years and included growth, hospital admissions, longstanding illness, wheezing, use of prescribed drugs, and parental rating of childrens health. In general, there was an inverse relationship between gestational age at birth and frequency of adverse health outcomes. The greatest number of such outcomes was among children born at moderate or late preterm (3236 weeks) or at early term (3738 weeks). Birth at 3236 weeks accounted for 5.7% of children with three or more hospital admissions at ages 9 months to 5 years. Birth before 32 weeks accounted for 3.8% of such children and birth at 3738 weeks for 7.2%. For a limiting longstanding illness, the corresponding population attributable fractions were 5.4% for birth at 3236 weeks, 2.7% for birth before 32 weeks, and 5.4% for birth at 3738 weeks.
In Bangladesh, a cluster randomized trial included 133 clusters (29,760 neonates) with randomization to one of three options: a single application of chlorhexidine to the cord soon after birth (single cleansing, SC); daily application for 7 days (multiple cleansing, MC); or dry cord care (DC). The UK Millennium cohort study is a nationally
Moderate or late preterm birth and health outcomes
Modestly preterm birth and early term birth contribute more to the burden of adverse health outcomes than does very preterm birth.
Bryle EM et al. Effects of gestational age at birth on health outcomes at 3 and 5 years of age: population based cohort study. BMJ 2012; 344 (March 17): 17 (e896).
Home treatment with oral amoxicillin was at least as effective as current WHO policy for severe pneumonia.
Soofi S et al. Effectiveness of community case management of severe pneumonia with oral amoxicillin in children aged 259 months in Matiari district, rural Pakistan: a cluster-randomised controlled trial. Lancet 2012; 379: 729737; Black RE, El Arifeen S. Communitybased treatment of severe childhood pneumonia. Ibid: 692694 (comment).
childs illness and may be a driving factor in fever phobia. Parents of children aged 06 were given an 18-question multiple choice questionnaire on fever management including the definition of fever based on body temperature, best place to take temperature, potential side effects of fever, drugs used for treatment, and drug administration techniques. The
Oral amoxicillin for severe early childhood pneumonia in rural Pakistan

In 2008, pneumonia accounted for 18% of all deaths in children under the age of 5 years. Almost half of all deaths in young children occur in Pakistan, India, China, Nigeria, and the Democratic Republic of the Congo. Delayed treatment is responsible for many child pneumonia deaths, and in 2004, the World Health Organization (WHO) and United Nations Childrens Fund recommended antibiotic treatment at home given by trained health workers, instead of hospital referral, for non-severe pneumonia in rural areas. Meta-analyses have confirmed the effectiveness of this policy. Now, a trial in rural Pakistan has shown that the policy is effective for children with severe pneumonia. A cluster randomized trial in rural Sindh province, Pakistan, included 4,410 children aged 259 months with WHO-defined severe pneumonia. The children were screened by lady health workers. Those with severe pneumonia were prescribed oral amoxicillin syrup (45 mg/kg twice daily) for 5 days at home (intervention clusters), or given a single dose of oral co-trimoxazole and referred to the nearest health facility for intravenous antibiotic treatment (control clusters). The children were followed up at 2, 3, 6, and 14 days. Treatment failure by day 6 occurred in 8% (intervention) and 13% (control), a non-significant difference. There were three deaths, two in the intervention group and one in the control group.
questionnaire was based on previous similar sur-
Paediatricians influence parental febrile behavior
veys and recent guidelines from the UK and Italy on fever management. Paediatricians were given a similar but terminologically different questionnaire. The majority of parents (67.8%) said that their paediatrician was their primary source of information on fever and fever management. All parents believed that fever could cause harmful effects like delirium, dehydration, or coma. If left untreated, 89.9% believed that fever could cause brain damage or seizures. The study highlighted a number of wrong behaviours. In similar ratios, paediatricians and parents said that they use sponging or ice packs to reduce fever (78.5% vs 77.8%; P = 0.867), and that they alternated ibuprofen and acetaminophen to treat fever (27% vs 21.4%; P = 0.953), despite guideline recommendations. Of concern, 1.4% of paediatricians and 1.2% of parents said that they use acetylsalicylic acid or steroids as a secondchoice therapy to antipyretic drugs (P = 0.937). Oral antipyretic administration was correctly preferred by 73.1% of paediatricians and 48.7% of parents ( P < 0.0001), compared with rectal administration. The similarities between many of the attitudes and practices related to fever demonstrate
Fever phobia describes an attitude of unreasonable fear that parents may have surrounding fever and treatment for fever in their children. A survey of 388 parents and 480 physicians from Italy showed that physician attitudes towards febrile children can inform how parents handle their
the degree to which parents follow their paediatricians lead. Educational programmes aimed at paediatricians could help modify parental behaviours as well.
Chiappini E et al. Parental and medical knowledge and management of fever in Italian pre-school children. BMC Pediatr 2012; 12(1): 97.
PA EDIA TRICS
Peer Reviewed
Imaging Paediatric Imaging Paediatric Brain Tumours Brain Tumours Paediatric Psoriasis
Tang Phua Hwee, MBBS, FRCR, MMed Diagnostic Radiology
Paediatric Psoriasis
Vyom Sharma, MBBS; David Orchard, MBBS, FACD
Tang Phua Vyom Hwee,Sharma, MBBS, FRCR, Diagnostic Radiology MBBS; MMed David Orchard, MBBS, FACD
INTRODUCTION
Psoriasis is a chronic inflammatory disease characterized by well-demarcated erythematous plaques that demonstrate a characteristic silvery scaling. About 3040% of adult cases begin by age 15. Early diagnosis and treatment can arrest progression to disfiguring states that requires extensive treatment, as well as minimize the psychosocial burden imposed by this illness. This article covers an approach to classification, provides some popular regimes treatment, and provides an up-to-date review of management options.
PATHOGENESIS AND AETIOLOGY

The aetiology of psoriasis is multifactorial. There is over- and under-expression of certain proteins in psoriatic lesions. The effects of these expressions are threefold: abnormal keratinocyte differentiation, hyperproliferation of the keratinocyte, and inflammatory infiltration. These actions are mediated by activated T cells and dendritic cells that are present in psoriatic plaques. These cells release pro-inflammatory cytokines which trigger a cascade of cytokines that lead to keratinocyte proliferation, neovascularization, and vasodilation. Much of psoriasis is believed to be mediated by tumor necrosis factor (TNF) a, a pro-inflammatory cytokine, of which increased levels are found in active plaques. Its role in active psoriasis is strongly suggested by increase in TNF levels after therapy and increased levels in psoriatic plaques.
JPOG JULY/AUG 2012 137
PAEDIATRIC S PAEDIATRICS
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Figure 1. Typical well-demarcated, salmon-pink patches with silvery scale.
Genetic influences are suggested by studies which state positive family history in first-degree relatives somewhere between 10% and 73%; however, more recent studies suggest figures of approximately 70%. Major gene for psoriasis susceptibility is thought mainly to be located on chromosome 6, the site of HLA class I (associated with early onset disease) and II (late onset disease) antigens which are thought to produce differing subtypes of the disease. However, environmental factors are believed to play a significant role in the development of the condition, suggested by twin studies demonstrating disparity in concordance, with only 35% of monozygotic twins demonstrating psoriasis. A highly relevant environmental factor is streptococcal infection, which has an established association with guttate-type psoriasis. It is postulated that streptococcal antigen activate lymphocytes which induces mitotic activity. However, certain individuals with the Cw*0602 allele are four times more likely to develop guttate psoriasis. Other noted associations are of an increased incidence of psoriasis seen in sufferers of Kawasaki disease, Crohns disease, ulcerative colitis and bone marrow transplantation, all supporting the im-
Figure 2. Psoriasis in the concha of the ear.
Figure 3. Napkin psoriasis.
munological basis for disease.
EPIDEMIOLOGY
One-third of adults with psoriasis report onset in childhood. Ethnic variation is not clear, with some studies quoting incidence highest in Caucasian, followed by black and then Asian populations. Other studies, however, noted no variance except in the Inuit race, postulating the role of omega-3 fatty acids in the prevention of psoriasis. Classically, some authors have observed female preponderance by 2:1; however, the larger
PA EDIA TRICS
PA ED IATRICS Peer Reviewed
studies showed approximately equal gender distribution. Age distribution in the paediatric population is unclear. The inclusion of psoriatic diaper rash drastically increases incidence of psoriasis in children under 2, the most common pattern of presentation in children of that age group. If excluded, however, studies show identical distribution amongst all age groups.
In babies, the napkin area is frequently involved (Figure 3). Psoriasis in this distribution will generally have no scale and the diagnosis is made on the salmon-pink colour of the erythema and the welldemarcated borders of the plaques. Itch is variable but mostly not a significant symptom. Differential diagnosis includes other papulosquamous disorders of childhood, including: atopic dermatitis, discoid eczema (nummular dermatitis), tinea corporis, lichen planus, drug reactions, pityriasis rosea, pityriasis rubra pilaris. Discoid (nummular) eczema (Figure 4a) tends to be more pruritic, is less well defined with more intensity towards the centre, and can be oozing. Tinea corporis (Figure 4b) tends to have a more active edge, and there will often be a history of gradual expansion. Pityriasis rosea (Figure 4c) may have a herald patch and have the oval lesions lining along the ribs, and the scale is described as trailing rather than leading the outer annulus. These diagnoses can be excluded with biopsy if there are difficulties with clinical diagnosis. If psoriasis is extremely aggressive, it may
DIAGNOSIS
Psoriasis primarily is diagnosed clinically and classified on the basis of morphology. It presents mostly as well-demarcated erythematous lesions with fine or coarse silvery scaling (Figure 1). The predominant areas affected are the knees, elbows, buttocks, and scalp although these areas are not as typically involved in the paediatric population as compared with adults. Certain sites when involved are highly suggestive of psoriasis and include the umbilicus (Figure 1), the concha of the ear (Figure 2), and the natal cleft. Isolated facial involvement can occur and is more common in the paediatric population than in adults. Intertriginous areas are also commonly affected in children possibly presenting as vulvitis, balanitis, and perianal itching.
Figure 4. Differential diagnosis. a. Discoid eczema. b. Tinea corporis. c. Pityriasis rosea.
Peer Reviewed
Figure 5. Pustular psoriasis requires hospitalization.
large studies. In the largest study of 1,262 cases in Australia, it composed 4050% of all cases. The thickness of the plaques and degree of scaling can be highly variable from patient to patient although is usually consistent from plaque to plaque on a given patient.
take on the form of pustular psoriasis (Figure 5). In this setting, there is frequently lethargy, fever, elevated white cell count, and elevated liver transaminases. The pustules are sterile, and children mostly will need medical admission and oral medication conducted by a dermatologist. Psoriasis severity is measured commonly by the Psoriasis Area and Severity Index (PASI) whereby four sections of the body (head, arms, trunk, and legs) are scored according to severity of psoriasis. The scores then multiplied by a factor which represents the proportion. While useful in trials, in clinical practice the calculations can be contrived with 16 separate variables. The simplified PASI for clinical use, whereby the severity of redness, thickness and scaling of all plaques on the body, are estimated on a scale of 14. Then, these three variables are each multiplied by the estimated percentage of body surface area covered by the plaques. These are then summed to give the simplified PASI.
Guttate Guttate (drop-like) psoriasis presents with a sudden onset widespread eruption of papules to small plaques. Together with plaque psoriasis, it constitutes the overwhelming majority of psoriasis cases. It is commonly precipitated by group A b-haemolytic streptococci infection or other viral infections. Swabbing of pharynx and perianal area is recommended by some, as subclinical Streptococcus infection can at times be present. Some authors recommend post-antibiotic urinalysis to monitor for post-streptococcal glomerulonephritis. Oral antibiotics can be used to treat the throat or perianal infection; however, they are not the mainstay treatment for psoriasis. Mucosal Involvement Mucosal involvement can involve up to 5.6% of cases. It can involve oral/genital mucosa which demonstrates erythematous patches. Therapy is not commonly needed. Nail Involvement Reports range from 7% to 40%. The changes that are most common are pitting, followed by onycholysis, longitudinal striations. Other changes include subungual keratosis and discolouration. Pustular This form is rare in children. It has explosive onset and high fevers and other constitutional symptoms. The morphology is different with often annular plaques with peripheral postulation. It will often recur, then be followed by a period of typical
CLINICAL SUBTYPES
Plaque Psoriasis Plaque psoriasis constitutes 3484% of cases in many
PA EDIA TRICS
plaque psoriasis. Complications such as elevated hepatic transaminases and Ig A nephropathy have been documented.
Table 1. Criteria for psoriatic arthritis proposed by Vasey and Espinoza
Criterion I: Psoriatic skin or nail involvement Criterion II: Peripheral pattern

1. Pain and soft tissue swelling with or without limitation of movement of the distal interphalangeal joint for over 4 weeks 2. Pain and soft tissue swelling with or without limitation of motion of the peripheral joints involved in an asymmetrical peripheral pattern for over 4 weeks. This includes a sausage digit 3. Symmetrical peripheral arthritis for over 4 weeks, in the absence of rheumatoid factor or subcutaneous nodules 4. Pencil-in-cup deformity, whittling of terminal phalanges, fluffy periostitis, and bony ankylosis
Non-pharmacological strategies including counselling about the natural history of the disease is important
Criterion III: Central pattern

Arthropathy Psoriatic arthropathy is rare in children; however, it can be debilitating. It can be difficult to distinguish psoriatic from rheumatoid arthropathy. The criteria devised by Vasey and Espinoza have proven to be most sensitive (Table 1). It commonly involves the proximal and distal interphalangeal joints of the feet, proximal interphalangeal joints of the hand, knees, and ankle. Over time, it involves the wrists, metacarpophalangeal joints, elbow, and metatarsophalangeal joints.
1. Spinal pain and stiffness with the restriction of motion present for over 4 weeks 2. Grade 2 symmetric sacroiliitis according to the New York criteria 3. Grade 3 or 4 unilateral sacroiliitis
fatty acid supplementation in adults has demonstrated marginal benefit. Trauma to the skin is well known to trigger a flare (Koebner phenomenon). Pharmacological triggers include chloroquine, hydroxychloroquine, lithium, b-blockers, or, more commonly used in children, withdrawal of systemic and potent topical steroids. The treatment varies significantly from patient to patient depending on impact of disease. It is reasonable to treat minimally in young children, who are not bothered by their condition, and with aggressive combination therapy in older children, if required. All treatments are considered to be suppressive rather than curative, and most therapies are additive in combination. It is often worthwhile using a combination of therapies and encouraging maximum compliance in an attempt to clear the
TREATMENT
Non-pharmacological strategies including counselling about the natural history of the disease is important, particularly regarding patient/family fears of permanent disfigurement. Stress has been implicated in adults as an exacerbator of disease severity. There is no clear research suggesting dietary triggers or therapy in children, although omega-3
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Table 2. Possible regimes

psoriasis and then maintaining with minimal or no therapy (Table 2).
Face and flexure LPC 2% + salicylic acid 2% in aqueous cream topically at night (coal tar solution) and hydrocortisone 1% ointment topically in the morning If refractory, consider addition of tacrolimus/pimecrolimus and/or bursts of more potent topical steroids. Scalp Shampoos containing corticosteroids, zinc, tar or salicylic acid or calcipotriol can be used. Topical therapy for plaque psoriasis affecting the trunk and limbs 1. Coal tar prepared 1% lotion topically nocte/BD or LPC (20% coal tar in alcohol solution) 4% + salicylic acid 2% in aqueous cream nocte/BD + moderately potent corticosteroid in the morning (both LPC and salicylic concentrations can be titrated up to 10%, based on response.) 2. Add calcipotriol 0.005% OD or BD. 3. Add tazarotene 0.05% at night + moderate steroid in the morning. 4. If the above fail, consider light therapy in older children, or biologics/systemic therapy (see below). (Seek dermatologic participation in management will be required.) Genital area 1. Hydrocortisone 1% BD 2. In cases of poor response after 2 weeks, a moderately potent corticosteroid cream applied OD. Younger children in nappies: Moderately potent corticosteroid cream and anti-candidal cream (nystatin/imidazole). Recent streptococcal throat infection To eliminate this precipitant, commence phenoxymethylpenicillin 12.5 mg/kg up to 500 mg orally BD for 10 days, or roxithromycin (immediate) or cephalexin if penicillin-sensitive When clear, LPC 12% in aqueous or zinc cream OD for maintenance. Acute pustular This presentation is serious and requires hospital admission.
BD = twice daily; LPC= liquor picis carbonis; OD = once daily.
All treatments are considered to be suppressive rather than curative
DISCUSSION OF MODALITIES
Topical Emollient: emollients are best used on scaling or irritated skin, and provide prompt relief. Greasier emollients are easiest to spread and are best for drier skin; however, a less greasy preparation may be best in hot weather. In order of increasing greasiness, preparations include: aqueous cream liquid paraffin, glycerol 10% in sorbolene cream, 50/50 liquid and white soft paraffin. Steroid: topical corticosteroids have antiinflammatory and anti-mitotic effects. The more potent preparations are used to treat thicker areas of skin. Facial and diaper region can be treated with mild preparations such as 1% hydrocortisone. Trunks and limbs can be treated effectively with medium- to high-potency steroids for limited periods of time. Adverse effects include atrophy in areas of thin skin, tachyphylaxis, striae, and hypothalamicpituitary-adrenal axis suppression. Coal tars: tar treatment has anti-inflammatory and antipruritic effects. It remains a popular choice in children because it obviates the systemic steroid absorption, although its odour and staining effects on skin affect compliance in older children. The preparations are in cream or liquid form. Its
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adverse effects include local acne, folliculitis, and irritant/contact dermatitis. When used as part of the Goeckerman regimen (daily topical coal tar and exposure to UV-A or UV-B), it has proven to be highly effective in many studies. However, it has concurrently demonstrated carcinogenic, potential increased mutagenicity and temporary genotoxicity; but a 20-year follow-up of 29 patients from Mayo Clinic did not find any cases of malignancies.
Emollients provide prompt relief of scaling or irritated skin.
Systemic therapies are usually reserved for chronic severe psoriasis refractory to topical and light therapies
Calcipotriene: this vitamin D derivative can be used where adverse effects of steroids, such as systemic absorption or atrophy, are of risk. Calcipotriene can be used as an adjunct, or less commonly as a substitute. Studies suggest equal or better response than topical steroids and anthralin with reduced side effects. However, maximal effect is initiated after 6 weeks only. Theoretical risk of hypocalcaemia is unlikely if calcipotriene is not used on large surface area. Calcineurin inhibitors: tacrolimus and pimecrolimus are calcineurin blockers. Tacrolimus is a calcineurin inhibitor that acts by preventing the production of cytokines in T cells and mast cells. While unsuitable for thick plaques owing to poor penetration and absorption, it has proven efficacious in the treatment of adults. A small paediatric study in 2007 of 11 patients showed drastic improvement
when applied to the face and intertriginous areas. Tazarotene: tazarotene is a topical synthetic retinoid best used as an adjunct to topical steroid and other therapies if control is not achieved. Local irritation is the only common side effect. Anthralin: anthralin use remains controversial in children. It can cause staining and troubling irritation. However, a study in children by Zvulunov on 58 children demonstrated remission in 81% and mild skin irritation in 20%. Use in children is rare and only as an adjunct.
SYSTEMIC
Systemic therapies are usually reserved for chronic severe psoriasis refractory to topical and light therapies. Safety of treatment beyond 1 years duration has not been well established.
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Coal tar medications remain a popular choice in children as they are considered to be safe.
There have been advances in the use of biologic therapies for paediatric autoimmune disease
Cyclosporin At doses of 35 mg/kg, cyclosporine has proven efficacious in paediatric psoriatic patients. Close monitoring for renal function and blood pressure is required. Theoretical risks of malignancy and lymphoproliferative disorders seem to be minimal owing to the low doses and limited durations of treatment in this population. Systemic Retinoid Acitretin and isotretinoin have proven beneficial as single agent therapy for pustular and erythrodermic psoriasis, however less so for plaque psoriasis. Side effects can include skin fragility, deranged liver enzymes, skeletal toxicity, and pseudotumor cerebri. Use as monotherapy is uncommon. It is often used as an adjunct to light therapy. Methotrexate Methotrexate (dosed at 0.20.7 mg/kg/wk) provides excellent clearance according to one study, conferring 75% PASI reduction in most children. Therapy is generally commenced with 7.5 mg and folate administration, with close monitoring of liver function tests and cholesterol. Common side effects include nausea and vomiting. It is a known abortifactant and teratogen, and can cause liver cirrhosis.
BIOLOGICS
Recently, there have been advances in the use of biologic therapies for paediatric autoimmune disease. Three TNF antagonist drugs have been commonly used in children for conditions such as Crohns disease and juvenile idiopathic arthritis. Owing to the recent development newness of these therapies, all potential side effects are not known.
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Psoriasis is believed to be mediated by tumor necrosis factor, of which increased levels are found in active plaques.
Etanercept A multicentre, randomized controlled trial has demonstrated efficacy versus placebo, with 53% of children achieving a physicians global assessment of clear by 12 weeks (versus 13% in the placebo group). Adverse events including human papillomavirus, infection, gastroenteritis and influenza were reported. Overall, it was well tolerated. It is given as subcutaneous injection once or twice weekly. Infliximab Infliximab is used for a variety of paediatric autoimmune diseases. Reports supporting infliximab in psoriasis include two case studies where both patients failed multiple therapies, topical and systemic with no side effects. Side effect profile in the treatment of other diseases has been encouraging, most commonly associated with upper respiratory
tract infection, pneumonia, but also rare cases of hepatosplenic lymphoma. It is administered as twoweekly intravenous infusion.
Adalimumab There is no literature on the use of adalimumab in paediatric psoriasis. However, it has demonstrated success in patients with juvenile idiopathic arthritis. Ustekinumab Ustekinumab is a human monoclonal antibody that inhibits interleukin receptor-mediated signalling. Multiple studies have demonstrated dose-dependent clinical responses and linear pharmacokinetics. Three recent randomized controlled trials have demonstrated 12-weekly subcutaneous ustekinumab to improve clinical and quality-of-life parameJPOG JUL/AUG 2012 145
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ters. Adverse event rates were favourable, with no indication of links with cardiovascular, malignancies, or infective morbidities. Ongoing studies shall provide data regarding adverse events over a longer period of time. These studies have not, however, been conducted in children, and as such their suitability and safety are yet to be assessed completely.
chological and emotional stress of this disease. Biologic modalities offer much promise for the efficacious and safe management of psoriasis in children.
2011 Elsevier Ltd. Initially published in Paediatrics and Child Health 2011;21(3):126131.
Further Reading LIGHT TREATMENT

UV-B UV-B has been demonstrated to be safe and efficacious in children. Narrowband therapy reduces dose of UV, and combination with topical/systemic modalities two to three treatments a week can be common. Side effects include erythema and hyperpigmentation. Carcinogenicity has not been demonstrated. PsoralenUV-A A psoralen is administered before UV therapy in this regime as a photosensitizer, either orally for generalized photosensitization or topically for local effect. However, psoralenUV-A therapy is uncommon since the advent of narrowband UV-B, as it has demonstrated an increased risk of squamous cell carcinoma and melanoma.
Dermatology Expert Group. Therapeutic guidelines: dermatology. Version 3. Melbourne: Therapeutic Guidelines Limited, 2009. Duffy DKL, Spelman LS, Martin NG. Psoriasis in Australian twins. J Am Acad Dermatol 1993;29:428434. Duvic M, Asano AT, Hagar C, Mays S. The pathogenesis of psoriasis and the mechanism of action of tazarotene. J Am Acad Dermatol 1998;4:S129S133. Fredriksson T, Pettersson U. Severe psoriasisoral therapy with a new retinoid. Dermatologica 1978;157:238244. Henseler T. The genetics of psoriasis. J Am Acad Dermatology 1997;37:S1S11. Lebwohl M, Ali S. Treatment of psoriasis. Part 1. Topical therapy and phototherapy. J Am Acad Dermatology 2001;45:487498. Lewkoweiz D, Gottlieb AB. Pediatric psoriasis and psoriatic arthritis. Dermatol Ther 2004;17:364375. Louden BA, Pearce DJ, Lang W, Feldman SR. A Simplified Psoriasis Area Severity Index (SPASI) for rating psoriasis severity in clinic patients. Dermatol Online J 2004;10:7. Morris A, Rogers M, Fischer G, Williams K. Childhood psoriasis a clinical review of 1262 cases. Pediatr Dermatol 2001;18:188198. Rasmussen JE. The relationship between infection with group A beta haemolytic streptococci and the development of psoriasis. Pediatr Infect Dis J 2000;19:153154. Raychaudhuri SP, Gross J. A comparative study of paediatric onset psoriasis with adult onset psoriasis. Pediatr Dermatol 2000;17:174178. Rogers M. Childhood psoriasis. Curr Opin Pediatr 2002;14:404409. US FDA. Highlights of prescribing information: Stelara ustekinumab). Available from: http://www.accessdata.fda.gov /drugsatfda_docs/label/2009/125261lbl.pdf.
CONCLUSION
Considering that a significant proportion of adult cases of psoriasis develops in children, it is important to diagnose and establish early management. Early intervention can maintain clearance, limit severity of the disease as well as reduce the psy-
About the Authors
Vyom Sharma is a hospital medical officer at the Royal Melbourne Hospital, Parkville, Melbourne, Australia. Conflict of interest: None. David Orchard is Staff Specialist in the Department of Dermatology, Royal Childrens Hospital, Melbourne, Victoria, Australia. Conflict of interest: None.
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Dysmenorrhoea Dysmenorrhoea
Shilpa Kolhe, MBBS, MD, MRCOG; Shilpa Deb, MBBS, DGO, MRCOG Shilpa Kolhe, MBBS, MD, MRCOG; Shilpa Deb, MBBS, DGO, MRCOG
BACKGROUND
Dysmenorrhoea is a medical condition characterized by severe uterine pain during menstruation manifesting as cyclical lower abdominal or pelvic pain, which may also radiate to the back and thighs. The term dysmenorrhoea is derived from the Greek words dys meaning difficult, painful or abnormal, meno meaning month, and rrhea meaning flow. It is commonly divided into primary dysmenorrhoea, where there is no coexistent pathology, and secondary dysmenorrhoea where there is an identifiable pathological condition known to contribute to painful menstruation. Symptoms of primary dysmenorrhoea begin a few hours before the start of menstruation and are often relieved during the first few days of bleeding. The initial onset of primary dysmenorrhoea is usually shortly after menarche (612 months), when ovulatory cycles are established. Secondary dysmenorrhoea can also occur at any time after menarche but is most commonly observed in women in their third and fourth decade of life in association with an existing condition. Since dysmenorrhoea is a symptom that could be perceived differently by different women, it is difficult to establish its true incidence. However, the reported prevalence is age-related, increasing from around 40% in girls aged 12 years, to 70% in girls at 17 years of age. An epidemiological study showed that the prevalence of dysmenorrhoea among adolescent females ranges from 60% to 93%, but decreases with advancing age. One systematic review of community and hospital surveys estimated the overall prevalence to be 4595% whilst a second age-based systematic review suggested 2550% of adult women and as many as 75% of adolescents experience pain with menJPOG JUL/AUG 2012 147
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struation. Pain is significant in 520% who report severe dysmenorrhoea or pain that prevents them from participating in their usual activities. One community survey of adolescents aged 1218 years showed dysmenorrhoea as one of the most common biomedical problems causing health risk behaviours and psychosocial problems, such as cigarette or alcohol use, dieting, infrequent/never seat belt use, and feeling depressed. It is one of the most commonly reported reasons for absenteeism from school or work with some studies suggesting that 1045% of women miss or reduce time at work, school or other activities. In the United States, the annual economic loss has been estimated at 600 million work hours and 2 billion dollars. These reports suggest a significant socio-economic and psychosocial impact of dysmenorrhoea on female health during the reproductive years.
strual cycle. (The hypothesis that prostaglandins released from the endometrium at the time of menses contribute to dysmenorrhoea is supported by the observation that endometrial concentrations of prostaglandin E2 (PGE2) and prostaglandin F2 (PGF2) correlate with the severity of dysmenorrhoea, that cyclo-oxygenase inhibitors decrease menstrual fluid prostaglandin levels and decrease pain, and that the clinical manifestations of dysmenorrhoea are similar to those with prostaglandin-induced labour or medical management of miscarriage. In contrast to the uterine contractions in normal menstruation, contractions in women with primary dysmenorrhoea often begin with elevate basal tone, reach higher active pressures (frequently more than 150 mm Hg), and are non-rhythmic or in coordinate. In addition to stimulating uterine contractions, PGF 2 and PGE 2 can cause contraction of bronchial, bowel, and vascular smooth muscle resulting in bronchoconstriction, nausea, vomiting, diarrhoea, and hypertension. Di-
PATHOPHYSIOLOGY
The most important physiological event reported with dysmenorrhoea is increased myometrial activity with accompanying uterine ischaemia (uterine angina), which stimulates the type C afferent pain neurones. Doppler flow studies have supported this hypothesis by showing higher uterine and arcuate artery resistance on the first day of menses in women with primary dysmenorrhoea than in controls. While the pathophysiological mechanisms that cause this are not entirely understood, it is thought that this myometrial activity is modulated and augmented by prostaglandin synthesis. This may reflect the increase in circulating levels of prostaglandin F 2, which is a potent myometrial stimulant and vasoconstrictor. It is also found that the levels of prostaglandins in endometrial fluid in the early follicular phase of menstrual cycle are less than levels in late luteal phase of menJPOG JUL/AUG 2012 148
arrhoea and nausea are commonly associated with primary dysmenorrhoea. The other reported factors in the causation of increased myometrial activity are increased levels of circulating vasopressin and leukotrienes. This effect is mediated via myometrial oxytocin and vasopressin V1a receptors. The role of vasopressin may relate to prostaglandin synthesis and release; leukotrienes, as well as PGE2, may increase the sensitivity of pain fibres in the uterus. Increased endometrial expression of leukotrienes has been demonstrated in women with primary dysmenorrhoea resistant to prostaglandin antagonists. Psychosocial factors may play a role in the perception and the severity of the pain.
CLINICAL FEATURES
History is critical in establishing the diagnosis of
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Table 1. Differential characteristics of primary and secondary dysmenorrhoea
Primary
Age (years) Onset of pain Pathophysiology Symptoms 1625 Just prior to menstruation (spasmodic) Excess prostaglandins, vasopressin, leukotrienes Usually self-limiting, lasts for first 13 days menstruation Responds to COCP and NSAIDs Periods normal or light Unremarkable
Secondary
3045 Pain often progresses through late luteal (congestive) Underlying disorder Associated with other features related to underlying disease Resistant to COCP and NSAIDs Periods often heavy Dependent on cause but may include a tender, enlarged, fixed, retroverted uterus with adnexal tenderness and a mass
Signs
COCP = combined oral contraceptive; NSAIDs = non-steroidal anti-inflammatory drugs.
dysmenorrhoea and also in differentiating between primary and secondary dysmenorrhoea. A thorough menstrual history including the age at menarche and at the onset of pain, cycle length and regularity, duration and amount of menstrual flow, and an assessment of the onset, duration, type, cyclicity and severity of pain and associated symptoms such as nausea, vomiting, bloating, diarrhoea and fatigue is essential in the diagnosis of dysmenorrhoea. It is then important to exclude the secondary causes of dysmenorrhoea such as pelvic infection, sexually transmitted disease, endometriosis, subfertility, abdominopelvic surgery and difficult childbirth which could present with additional symptoms of deep dyspareunia, intermenstrual, postcoital bleeding, and subfertility. One should specifically determine the factors that exacerbate or ameliorate the symptoms, as secondary dysmenorrhoea is more commonly refractory to simple treatments such as non-steroidal anti-inflammatory drugs (NSAIDs) and the combined oral contraceptive (COCP). Social and family history should be considered as they may have direct or indirect bearing on the causation and help in optimizing the treatment (Table 1).
PRIMARY DYSMENORRHOEA
Primary dysmenorrhoea almost invariably occurs in young women with ovulatory cycles and usually appears within a year after menarche. The pain classically begins just before or with the onset of menstruation lasting through the first 12 days and is typically described as spasmodic lower abdominal or pelvic pain superimposed over a constant dull aching pain, which may radiate to the back and along the thighs. Menstrual bleeding is usually normal. Associated symptoms such as malaise and fatigue (85%), irritability (72%), dizziness (28%), headache (45%), lower backache (60%), diarrhoea (60%), and nausea and vomiting (89%) may be present. The diagnosis of primary dysmenorrhoea is made primarily based on history and then by exclusion of existing pathology. Pelvic or rectal examination where appropriate may be helpful to exclude common problems of young age such as pelvic inflammatory disease and endometriosis, and provide reassurance through a negative assessment. Psychosexual factors may be contributing to dysmenJPOG JUL/AUG 2012 149
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orrhoea and should be considered where medical treatment is unsuccessful.
menorrhoea is endometriosis. Women with endometriosis who present with secondary dysmenorrhoea have physical findings approximately 40% of the time. It is important to remember that absence of abnormal findings does not exclude secondary dysmenorrhoea and should be complemented with a transvaginal ultrasound. A small but significant minority of adolescent girls will have secondary dysmenorrhoea, which is largely due to endometriosis, ovarian cyst or presence of congenital anomaly in the urogenital tract. Endometriosis may be an isolated finding or associated with a uterine abnormality, which is more likely when dysmenorrhoea occurs during the first or second cycles after menarche. Adnexal, rectovaginal and uterine tenderness associated with cervical excitation is seen in 76% of adolescents with endometriosis, reiterating the importance of pelvic examination in this group of patients. More extensive disease will manifest similarly to that seen in older women with nodular disease over the uterosacral ligaments and rectovaginal septum, decreased uterine mobility, and unilateral or bilateral adnexal masses. Similar findings may be seen in adolescents with acute or chronic pelvic inflammatory disease.
SECONDARY DYSMENORRHOEA
Secondary dysmenorrhoea mainly occurs in the third and fourth decade of reproductive life. The pain is different to that of primary dysmenorrhoea and is described as pelvic heaviness and back pain increasing progressively throughout the late luteal phase and peaking with the onset of menstruation. This pattern of pain is often referred to as congestive pain in contrast to the spasmodic pain seen with primary dysmenorrhoea. The pain associated with secondary dysmenorrhoea is more likely to coincide or be temporally associated to other gynaecological symptoms, such as cycle irregularity, heavy periods, dyspareunia, vaginal discharge, intermenstrual bleeding, and postcoital bleeding.
Major Causes of Secondary Dysmenorrhoea Gynaecologic disorders: Endometriosis Adenomyosis Pelvic inflammatory disease Fibroids Endometrial polyps Ovarian cysts Intrauterine contraceptive device Intrauterine adhesions Congenital obstructive mullerian malformations Pelvic congestion syndrome Cervical stenosis Non-gynaecologic disorders: Inflammatory bowel disease Irritable bowel syndrome Urogenital disease Psychogenic disorders The most common cause of secondary dysJPOG JUL/AUG 2012 150
INVESTIGATIONS
Careful analysis of the clinical findings should be made and investigations directed towards the likely underlying causes. There are no specific tests to diagnose primary dysmenorrhoea, which is largely made on clinical findings. Routine blood tests are not usually indicated in patients with isolated dysmenorrhoea, but a full blood count to exclude anaemia should be undertaken in women with associated menorrhagia. Microscopy and culture of swabs from the endocervix for Chlamydia and gonorrhoea should be obtained together with a high vaginal swab
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from the posterior vaginal fornix for other sexually transmitted diseases. A raised white cell count suggests infection and may be associated with a raised erythrocyte sedimentation rate and C-reactive protein in patients with chronic pelvic inflammatory disease. These tests are non-specific but may be used to monitor disease progression or response to therapy. The same is true of the tumour marker CA-125, which is raised in some cases of endometriosis. Underlying causes of secondary dysmenorrhoea such as fibroids, intrauterine contraceptive devices and ovarian cysts including endometriomas are best assessed with ultrasound. Transvaginal ultrasound is preferable to transabdominal as it offers more resolution and can also be used as an extension of the pelvic examination to qualify tenderness and uterine mobility. To improve the sensitivity and specificity of ultrasound in the detection of endometrial lesions including polyps and submucosal fibroids, consideration should be given to saline infusion sonography, which is shown to be comparable with hysteroscopy in diagnosing endometrial lesions (Tables 1 and 2). Three-dimensional ultrasound offers the benefit of assessing organs in coronal plane and, therefore, can prove beneficial in the diagnosis of endometrial pathology. Four-dimensional ultrasound may have a role in assessing the frequency and intensity of myometrial activity associated with dysmenorrhoea. In certain cases, to ascertain or clarify diagnosis, a diagnostic laparoscopy may be required. Laparoscopy is the gold standard in investigation of peritoneal endometriosis, adhesions and chronic pelvic inflammatory disease, also allowing treatment at the same time. Hysteroscopy may be indicated to evaluate intrauterine pathology suggested by imaging and may be combined with resection of an endometrial polyp or sub-mucosal fibroid.
Table 2. Evidence-based treatment options for dysmenorrhoea
Grade A NSAIDs (other than aspirin) Combined oral contraceptives Grade B & C Aspirin, paracetamol, and compound analgesics Magnesium Thiamine Vitamin B1, B6, E Fish oil High-frequency TENS Topical heat (about 39C) Exercise Japanese and Chinese herbal medicine Unknown Levonorgestrel intrauterine system Surgical interruption of pelvic nerve pathways Acupuncture Behavioural interventions Magnet therapy Vasopressin antagonists Low-frequency TENS No benefit Spinal manipulation
NSAID = non-steroidal anti-inflammatory drug; TENS = transcutaneous electrical nerve stimulation.
MANAGEMENT
Treatment for dysmenorrhoea is aimed at relieving symptoms and is best treated with analgesics that are prostaglandin inhibitors so as to affect the physiological mechanisms behind menstrual pain and by directing treatment at the underlying pathology. Many studies have employed patient self-reporting using a visual analogue or other pain scale, quality of life scales, or other similar measures such as the menstrual distress or menstrual symptom questionnaires. Additional measures include analysis of the proportion of women requiring analgesics in addition to their assigned treatment and recording the percentage of women reporting activity restriction of social activities or absenteeism from work or school. Whichever system is used, grading dysmenorrhoea according to severity of
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pain and limitation of daily activity will help guide the treatment strategy and catalogue the response to treatment (Table 2).
Cox-2 inhibitors are more expensive. It should be remembered, however, that NSAIDs are associated with adverse effects including headache, drowsiness, dizziness and dryness in addition to gastrointestinal effects like nausea and indigestion. Gastrointestinal ulceration and haemorrhage were less prominent side effects, probably owing to the short-term administration only. When treating women with risk factors for NSAID-induced ulceration which include previous clinical history of gastroduodenal ulcer or perforation, gastrointestinal bleeding, or the concomitant use of medications known to increase the likelihood of upper gastrointestinal adverse events, such as corticosteroids and anticoagulants the potential risks and benefits of using an NSAID should be considered and discussed with the patient. If an NSAID is offered in this situation, a gastro-protective agent should also be prescribed. NSAIDs are also contraindicated in patients with renal insufficiency, bleeding diatheses, and aspirin hypersensitivity because of their pharmacokinetic and pharmacodynamic drug interactions and possible effects on platelet aggregation. However, because they are generally used for short periods in otherwise healthy young women, they are frequently well tolerated and free of serious toxicity in most patients. It is unclear which NSAIDs have better efficacy or safety and when is the optimal time to initiate treatment. While all NSAIDs are thought to be effective, relieving pain by up to 70%, naproxen and ibuprofen appear significantly better than mefenamic acid and aspirin in terms of the need for rescue analgesia. NSAIDs that achieve peak serum concentrations within 3060 minutes and have a faster onset of action (eg, ibuprofen, naproxen, meclofenamate) may be preferred. Some recommended doses are as follows: naproxen 250275 mg four to eight hourly; ibuprofen 400 mg three,
Medical Treatments
NSAIDs (Other Than Aspirin)
NSAIDs are the mainstay of treatment for primary dysmenorrhoea. It is proposed that NSAIDs relieve primary dysmenorrhoea mainly by suppressing the production of endometrial prostaglandins, thus alleviating cramps and restoring normal uterine activity. In addition, there may be direct analgesic action on the central nervous system (Dawood 2006). NSAIDs inhibit cyclooxygenase (Cox) type 1 and 2 pathways, thus inhibiting synthesis of prostaglandins. A recent Cochrane review analysed 73 randomized controlled trials (RCTs). Nineteen different types of Cox-1 NSAIDs and two Cox-2 NSAIDs (meloxicam and etoricoxib) were evaluated. NSAIDs (with an exception of aspirin) were significantly superior to placebo in reducing the pain associated with primary dysmenorrhoea (odds ratio, OR, 4.50; 95% confidence interval, CI, 3.85 5.27). NSAIDs were also significantly more effective for pain relief than paracetamol (OR, 1.90; 95% CI, 1.053.44). NSAIDs with the exception of Cox-2 inhibitors may also benefit social interaction, with evidence from one systematic review that their use is associated with a reduced restriction of daily activities, absenteeism, and the need for additional analgesia compared with placebo. When NSAIDs were compared with each other, there was no significant difference found in their efficacy (P > 0.05). Etoricoxib did not differ significantly in efficacy from naproxen, and meloxicam was significantly less effective for pain relief than diclofenac. Although known to have reduced gastrointestinal toxicity, neither Cox-2 NSAIDs differed significantly in tolerability from the Cox-1 comparators. Besides,
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four or six times daily; diclofenac 200 mg/day in divided doses; mefenamic acid 250 mg eight hourly; nimesulide 50100 mg twice daily; meloxicam 7.515 mg daily. Pareek et al found that fixed-dose combination of aceclofenacdrotaverine (NSAID + antispasmodic) was superior to monotherapy with aceclofenac in women with primary dysmenorrhoea. Another RCT concluded that one to two tablets of combination of ibuprofen and paracetamol provided superior analgesic efficacy than placebo.
Aspirin, Paracetamol and Compound Analgesics
and, therefore, the oestrogen-dependent proliferation of the endometrium and reduced secretion of progesterone. This in turn reduces the amount of prostaglandin produced by glands in the lining of the uterus, which then reduces both uterine blood flow and cramps. A Cochrane systematic review of the efficacy of COCPs for primary dysmenorrhoea analysed 10 RCTs out of the 23 identified. Improvement in pain was reported in five studies that compared COCP to placebo (OR, 2.01; 95% CI, 1.323.08). Combined oral contraceptive pills containing less than 35 g of oestradiol have been shown to control symptoms of dysmenorrhoea effectively and therefore should be the preferred choice of COCP. There is strong evidence to support the use of COCPs containing low-dose oestrogen for the treatment of dysmenorrhoea. Tricycling COCP has been used to treat women with severe dysmenorrhoea especially that associated with endometriosis. The extended cycle regimen might be associated with less menstrual pain than the monthly regimen. However, future trials comparing the two regimes are warranted. A Cochrane systematic review on the efficacy of modern COCP (low-dose oestrogen) found COCP as effective as gonadotrophin-releasing hormone analogue in treating painful symptoms of endometriosis. Transdermal and vaginal ring contraceptives have a favourable impact on dysmenorrhoea similar to that noted with the use of COCP. There were no studies identified that directly compared COCP to NSAIDs in the management of dysmenorrhoea.
Other Hormonal Therapies
Paracetamol was shown to offer no additional pain relief than placebo, aspirin or naproxen in two systematic reviews. Coproxamol (paracetamol and dextropropoxyphene) appears to be superior to placebo, but is associated with more side effects than naproxen and is less effective than mefenamic acid. One systematic review found that aspirin was significantly more effective than placebo for pain relief but not as effective as ibuprofen, naproxen and mefenamic acid (number needed to treat for aspirin was 10, compared with only 2 or 3 for other NSAIDs).
Combined Oral Contraceptives
COCPs are commonly used as second-line therapy for primary dysmenorrhoea where NSAIDs are ineffective, poorly tolerated or contraindicated. Over 90% of adolescents with primary dysmenorrhoea report a reduction in pain within 3 months of commencing a COCP containing at least 30 g of oestrogen. Zahradnik et al suggested that COCPs should be used as a first-line therapy in women with dysmenorrhoea who also wish contraception. This method of approach eliminates the risks associated with taking NSAIDs for pain relief. COCP is thought to work by inhibiting ovulation
Other hormonal therapies such as progestogens (depomedroxyprogesterone acetate and levonorgestrel), danazol and gonadotrophin-releasing hormone analogues again work by inhibiting ovulaJPOG JUL/AUG 2012 153
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tion and suppressing the menstrual cycle and can occasionally be used for resistant dysmenorrhoea. They are frequently used for short periods of no more than 6 months to provide a few months of amenorrhoea and relief from symptoms in women debilitated by their pain. The levonorgestrel-releasing intrauterine system, although not licensed for the treatment of dysmenorrhoea, can be of benefit in treating coexistent menorrhagia.
the benefits of magnesium; however, the results of three small trials comparing magnesium with placebo showed that magnesium was more effective than placebo for pain relief and the need for additional medication was less. The dose and regimen of treatment with magnesium to be used is still unclear. Pyridoxine pyridoxine (vitamin B 6) is shown to be more effective at reducing pain when compared with placebo and a combination of magnesium and vitamin B 6. Omega-3 fatty acids (fish oil) one RCT has shown that the use of omega-3 fatty acids may reduce pain, although more research is needed to quantify this effect. Adverse effects associated with fish oil treatment were mild and included nausea and worsening of acne. Vitamin B 1 one large trial showed vitamin B 1 to be more effective than placebo in reducing pain. Vitamin E a RCT showed vitamin E alone (500 units per day or 200 units twice per day, beginning 2 days before menses and continuing through the first 3 days of bleeding) was more effective than placebo for relieving dysmenorrhoea in adolescents randomly assigned to either therapy, although both active drug and placebo reduced pain. Japanese herbal medicine one small trial showed the natural herbal remedy tokishakuyaku-san to be more effective for pain relief than placebo and less use of additional pain medication. There is some evidence supporting the benefits of a low-fat vegetarian diet on dysmenorrhoea in parous women. Chinese herbal medicine there is some promising evidence supporting the use of Chinese herbal medicine for primary dysmenorrhoea. However, results are limited by the poor methodological quality of the trials.
Surgical Treatments Surgical intervention may be necessary to treat the underlying cause of secondary dysmenorrhoea. It is generally not indicated for treating primary dysmenorrhoea. Although there is insufficient evidence to support its routine use, surgical procedures such as laparoscopic uterine nerve ablation and presacral neurectomy may be performed for symptomatic relief of pain in refractory cases of dysmenorrhoea. These two surgical procedures interrupt most of the cervical sensory nerve fibres (thus diminishing uterine pain). Dependent upon the aetiology, this may necessitate conservative laparoscopic or open surgery with adhesiolysis, ovarian cystectomy, salpingectomy and ablation or excision of endometriotic deposits or hysteroscopic resection of endometrial polyps, intrauterine adhesions and sub-mucosal fibroids. In severe cases of endometriosis resistant to medical therapy, hysterectomy, with or without bilateral oophorectomy, may be required. Conservative Treatments
Herbal Products and Dietary Supplements
Thiamine a single large randomized controlled trial has shown beneficial effects of thiamine (100 mg daily) on menstrual pain when used for 2 months or more. A total of 87% of patients were cured up to 2 months after treatment. Magnesium there is limited evidence on
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Alternative remedies
Acupuncture there is limited evidence from controlled trials to support the use of complementary alternative medicine (acupuncture, yoga) for treatment of dysmenorrhoea. Three trials compared acupuncture to sham acupuncture; all three observed a reduction in pain in both groups, but only one trial noted greater pain reduction in the real versus the sham acupuncture group. More data from controlled trials demonstrating safety and efficacy need to be done before these modalities can be recommended. Spinal manipulation spinal manipulation may improve spinal mobility and pelvic blood flow, hence reducing menstrual pain. This has been reported as an effective alternate treatment for dysmenorrhoea in two small, limited-quality RCTs. A larger and better designed RCT found no significant difference between spinal manipulation and placebo manipulation after 1 month. Overall, there is no evidence to suggest that spinal manipulation is effective in the treatment of primary or secondary dysmenorrhoea.
Other Non-hormonal Therapies
Exercise systematic review on the use of exercise for relief of dysmenorrhoea included a single randomized trial that provided some evidence that exercise reduces menstrual symptoms. Topical heat treatment heat to abdomen appears to be as effective as oral analgesics for relief of dysmenorrhoea. A trial randomly assigned women with dysmenorrhoea to an abdominal heat wrap (40C) which was worn for 8 hours, a placebo wrap, acetaminophen (1,000 mg every 5 hours, four times per day for 1 day), or placebo pills. The heat wrap provided better pain relief than acetaminophen and was well tolerated. Transcutaneous electrical nerve stimulation transcutaneous electrical nerve stimulation (TENS) seems to work by altering the bodys ability to receive or perceive pain signals. TENS is thought to have two effects: (1) it raises the threshold for pain signals from uterine hypoxia and hypercontractility by sending a volley of afferent impulses through the large diameter sensory fibres of the same nerve root, resulting in lower perception of painful uterine signals; and (2) it stimulates release of endorphins from the peripheral nerves and the spinal cord. A meta-analysis from the Cochrane database including three trials (n = 124 women) found that high-frequency (50120 Hz) TENS was more effective than placebo TENS for relief of dysmenorrhoea but is less effective than ibuprofen. Behavioural interventions a systematic review concluded that behavioural interventions may be of benefit in treating women with dysmenorrhoea. These include attempts at modification of the way the woman thinks about her pain (eg, desensitization-based procedures, hypnotherapy, imagery, coping strategies) and attempts at modification of her response to pain (eg, biofeedback, electromyographic training, Lamaze exercises, and relaxation training).
Alverine citrate, an anticholinergic antispasmodic, is licensed for the treatment of dysmenorrhoea, but there is a lack of published evidence on its efficacy for this indication and it is unlikely to be as effective as NSAIDs or the COCP. Beta-agonists and calcium channel blockers are reported to be of some benefit in dysmenorrhoea, but none is licensed for this indication. Transdermal glyceryl trinitrate is useful as a modulator of uterine contractility and an alternative for the management of primary dysmenorrhoea, although is limited by its side effect of headache. There are trials underway assessing the role of vasopressin antagonists, antispasmodics, magnesium, vitamin K, and magnet therapy in the treatment of dysmenorrhoea.
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Practice points
supportive providing symptomatic relief, and more directive surgical treatment should be reserved for specific secondary causes of dysmenorrhoea or for refractory cases.
2011 Elsevier Ltd. Initially published in Obstetrics, Gynaecology and Reproductive Medicine 2011;21(11):311316.
Around 4070% of women suffer with dysmenorrhoea Increased myometrial activity induced by an excessive production of prostaglandin causing ischaemia is the most accepted pathophysiological mechanism Primary dysmenorrhoea is seen in young women with ovulatory cycles and is characterized by spasmodic menstrual pain starting just before menstruation lasting for 2448 hours. There is no coexisting pathology Secondary dysmenorrhoea is always associated with an underlying pathology and is characterized by congestive menstrual pain, which increases progressively through the late luteal phase, peaking with onset of menstruation History is critical in establishing the diagnosis of dysmenorrhoea Treatment is aimed at symptomatic relief with analgesics especially NSAIDs and at treating the underlying pathology
Further Reading
Chantler I, Mitchell D, Fuller A. The effect of three cyclo-oxygenase inhibitors on intensity of primary dysmenorrheic pain. Clin J Pain 2008;24:3944. Cho SH, Hwang EW. Acupuncture for primary dysmenorrhoea: a systematic review. BJOG 2010;117:509. Tugay N, Akbayrak T, Demirturk F, et al. Effectiveness of transcutaneous electrical nerve stimulation and interferential current in primary dysmenorrhea. Pain Med 2007;8:295 300.
Cochrane Reviews PROGNOSIS

There are very few longitudinal studies examining the progression and eventual outcome of primary or secondary dysmenorrhoea. Primary dysmenorrhoea often improves in the third decade of a womans reproductive life and appears to be reduced after childbirth. The prognosis of secondary dysmenorrhoea is not known, as its severity, progression and eventual outcome depend on the underlying pathology.
Brown J, Brown S. Exercise for dysmenorrhoea. Cochrane Database Syst Rev 2010;(2):CD004142. Herbal and dietary therapies for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev 2002. Marjoribanks J, Proctor ML, Farquhar C. Nonsteroidal antiinflammatory drugs for primary dysmenorrhoea. Cochrane Database Syst Rev 2010;(1):CD001751. Proctor ML, Hing W, Johnson TC, Murphy PA. Spinal manipulation for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev 2006;(3):CD002119. Proctor ML, Latthe PM, Farquhar CM, Khan KS, Johnson NP. Surgical interruption of pelvic nerve pathways for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev 2005;(4):CD001896. Proctor ML, Murphy PA, Pattison HM, Suckling J, Farquhar CM. Behavioural interventions for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev 2007;(3):CD002248. Wong CL, Farquhar C, Roberts H, Proctor M. Oral contraceptive pill for primary dysmenorrhoea. Cochrane Database Syst Rev 2009;(4):CD002120.
CONCLUSIONS
Dysmenorrhoea has a significant physical, behavioural, psychological and social impact, affecting 4070% of women of reproductive age. It is a leading cause of absenteeism. The exact pathophysiological processes are not fully understood, but it probably reflects increased myometrial activity induced by an excessive production of prostaglandin causing ischaemia. Mainstay treatment is generally
About the Authors

Shilpa Kolhe is a Senior Registrar in Obstetrics and Gynaecology at Queens Medical Centre, Nottingham, UK. Conflicts of interest: None declared. Shilpa Deb is a Consultant in Obstetrics and Gynaecology at Nottingham University Hospitals NHS Trust, Queens Medical Centre Campus, Nottingham, UK. Conflicts of interest: None declared.
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What Are the Benefits and Risks of HRT?

Elizabeth Farrell, AM, FRANZCOG, FRCOG
ormone replacement therapy (HRT) is the most effective treatment for menopause symptoms in peri- and postmenopausal women, in particular for the vasomotor symptoms of hot flushes and sweats and symptoms relating to the atroph-
ic changes in the urogenital tract. Over-the-counter alternative products have no better effect than placebo. About 20% of women will have moderate to severe symptoms that interfere with quality of life, and longitudinal studies have shown that significant symptoms may last up to a mean of 8 years, with about 10% of women affected having symptoms for 10 years or more. Opinions concerning the benefits and risks of HRT have varied over the past decade. This article aims to summarize the current position, as given in the most recent recommendations of the International Menopause Society.1 All menopausal women should be advised to develop a healthy lifestyle programme in addition to possibly taking HRT. This lifestyle plan should include healthy eating, cessation of smoking, limiting alcohol intake, being a healthy weight, and undertaking regular exercise, and will depend on the age of the woman at the time of her menopause.
INDICATIONS FOR HRT

The indications for prescribing HRT are the presence of moderate to severe menopausal symptoms impacting on a womans ability to function normally, and as a first-line therapy in young women with osteoporosis.
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All menopausal women should develop a healthy lifestyle, in addition to possibly taking hormone replacement therapy.
yearly after her regimen is effective in improving her symptoms and quality of life. Regular screening is recommended, with a yearly riskbenefit analysis being made. The duration of therapy should not be fixed but reassessed yearly. HRT can be ceased every 4 to 5 years to see if symptoms recur; it may be required for 5 to 10 years, or perhaps longer.
PREMATURE AND EARLY MENOPAUSE

Women experiencing a premature menopause (before the age of 40 years) or an early menopause (before the age of 45 years) are at greater health risks of early onset of osteoporosis, cardiovascular disease and perhaps also an increase in mood disorders and dementia. It is usually advised that these women take HRT at least until they are 50 years of age. These younger women often require high-dose therapy, either HRT or the oral contraceptive pill, for effective symptom control and to preserve bone density.
HRT PRESCRIBING
The HRT products available include tablets, patches, and gels. Recently, there has been a reduction in the number of products available for women because pharmaceutical companies have withdrawn various products for financial reasons (not because Some of the menopause symptoms women experience are listed in the box on page 159. of any safety issues). The dose of HRT prescribed should be the lowest effective dose that reduces symptoms and improves quality of life, but should always be individualized, sometimes requiring up to 6 months A woman who is prescribed HRT should be reviewed after 2 to 3 months, have her regimen tailored over further visits and then be seen at least
MONITORING OF PATIENTS ON HRT
to determine the appropriate combination of hormones. Combined therapy of oestrogen and a pro-
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gestogen (E+P) should be prescribed in women with a uterus, and oestrogen alone (oestrogen replacement therapy; ERT) in women who have had hysterectomies. Cyclical progestogens (E+P) are used in perimenopausal cycling women and continuous progestogen (E+P) after menopause. Tibolone is another option for postmenopausal women. Urogenital symptoms can be treated appropriately with vaginal oestrogen therapy either alone or in combination with HRT.
Menopause symptoms1
Hot flushes in 80% women significant in 20% of affected women last longer than 5 years in 25% of affected women Night sweats Muscle/joint pains Formications Anxiety, irritability Sleep disturbances Lessened memory, concentration Vaginal dryness, low libido Fatigue Overall diminished wellbeing
A recent follow-up study of the WHI showed a reduced risk of breast cancer in the women who took oestrogen alone for 7 years
various medical conditions, such as breast cancer, will also vary within our population, depending on a womans country of origin and the length of time she has lived in Australia.
NEW MESSAGE ABOUT HRT NEAR MENOPAUSE

In 2007, the Womens Health Initiative (WHI) investigators reanalysed their data about coronary heart
So-called bioidentical or natural HRT products, which are formulated from imported hormones by local compounding pharmacies, are untested for long-term safety and efficacy and avoid the safeguards of Therapeutic Goods Administration registration. They are a potential medicolegal hazard for prescribers and should not be advocated. Most studies in women using HRT have been in western industrialized countries with mainly Caucasian populations. The research literature needs to be interpreted accordingly and may not necessarily be applicable to all community groups. The incidences of menopause symptoms and of
disease (CHD) that had lead to scare headlines in 2002.2 They found that there was an absence of excess risk of CHD and the suggestion of reduced total mortality in younger women. This offered reassurance to those women initiating HRT under the age of age 60 years for symptom control. No morbidity was significantly increased in this group, which is the group normally treated with HRT. Meta-analysis of other studies supports this conclusion. A recent follow-up study of the WHI showed a reduced risk of breast cancer in the women who took oestrogen alone for 7 years. This is also reassuring for these women.3
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Each woman should be counselled about the benefits and risks of hormone replacement therapy to enable her to make an informed decision.
BENEFITS AND RISKS OF HRT

Benefits
HRT has the following beneficial effects: relieves vasomotor symptoms of hot flushes and sweats reverses urogenital atrophic symptoms, such as vaginal dryness, loss of lubrication prevents bone loss due to oestrogen deficiency associated with menopause decreases osteoporosis fractures in the spine and hip reduces risk of diabetes improves connective tissues in skin, joints, arteries, and intervertebral discs. If HRT is commenced in healthy women around the time of the final menstrual period, there may be a reduction in cardiovascular risk and a reduction of Alzheimers dementia. HRT may have beneficial effects on the followJPOG JUL/AUG 2012 160
ing menopause symptoms: aches and pains in joints and muscles insomnia or sleep problems loss of libido mood disturbance quality of life. HRT may also improve sexual function, and the specific HRT conjugated equine oestrogens plus medroxyprogesterone acetate when used for more than 4 years may reduce the risk of colon cancer.
Risks
Most studies on the risks of HRT focus on the risks of cancer associated with its use. Risks of specific cancers and of other conditions are summarized below.
Breast Cancer
The WHI study has shown no increase in the risk of breast cancer in first-time E+P HRT users 5 years
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after treatment initiation. It has shown a small increase 4 to 5 years after treatment initiation in those with prior use (less than 0.1% per year or fewer than 1 per 1,000 women per year of use). The WHI and the Nurses Health Study have shown that there was no increase in risk of breast cancer after 7 to 15 years of use of ERT.
Hormone replacement therapy is the most effective treatment for menopause symptoms in peri- and postmenopausal women.
If HRT is commenced in healthy women around the time of the final menstrual period, there may be a reduction in cardiovascular risk and a reduction of Alzheimers dementia
Little information is available on different doses, routes of administration of oestrogen, progesterone, progestogens, and androgens. Cessation of HRT leads to a lowering of risk, and after 5 years the risk is the same as the general population of the same age. Mammographic breast density is increased with HRT, and this may decrease the ability to interpret mammograms accurately.
Endometrial Cancer
proliferative effect of oestrogen. An adequate progestogen dose will reduce the risk of endometrial hyperplasia and cancer. Tibolone use is not associated with an increase in the risk of hyperplasia or endometrial cancer.
Ovarian Cancer
The risk of endometrial cancer is increased in women with an intact uterus taking unopposed oestrogen therapy. The risk will increase with increasingly higher doses of oestrogen and will remain for many years even after the oestrogen has been stopped. Therefore, women should always be given a progestogen to protect the endometrium against the
There is no evidence showing an increased risk of ovarian cancer in women taking combined HRT. A very small increase in risk has been shown with long-term oestrogen-only therapy.
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Most studies on the risks of hormone replacement therapy focus on the risks of cancer associated with its use.
Lung Cancer
Stroke
A statistically significant small increase in the risk of non-small cell lung cancer has been shown in older women taking HRT for 5 years, but there was no increased risk in women in the 50- to 59-year-old group.
Coronary Artery Disease
The age of the woman, her cardiovascular risks (such as hypertension) and the route of administration of E+P or ERT are all factors that influence the risk of stroke. The WHI and the Nurses Health Study both showed an increase in risk in women taking oral E+P or ERT of one additional stroke per 1,000 person-years. In an observational study, transdermal oestradiol at doses of 50 g or less showed no increase in risk of stroke. Tibolone is associated with a small increase in risk of stroke in older women.
Venous Thromboembolism
Increasing age at time of initiation of HRT has been shown to lead to increased risk of coronary events, especially in older women with pre-existing coronary disease. The events are increased in the first year of therapy. No increased risk of coronary events was shown when HRT was initiated near the menopause, and there may even be possible protection.
Venous thromboembolism (VTE) is the major risk associated with the taking of oral oestrogens. The
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risk also increases with increasing age, obesity, and thrombophilias, and may vary according to the type of progestogen being taken. Transdermal oestrogens seem to have a lower risk of VTE, related to the avoidance of the first-pass pathway of metabolism. Tibolone is not associated with an increased risk of VTE.
Alzheimers Dementia
Each woman should be counselled about the benefits and risks of HRT in a manner that allows her to make an informed decision. Written or website information will also help her to confirm her decision.
FURTHER READING
Anderson GL, Limacher M, Assaf AR, et al; Womens Health Initiative Steering Committee. Effects of conjugated equine oestrogen in postmenopausal women with hysterectomy: the Womens Health Initiative randomized controlled trial. JAMA 2004:291:17011712. Collins P, Rosano G, Casey C, et al. Management of cardiovascular risk in the perimenopausal women: a consensus statement of European cardiologists and gynecologists. Climacteric 2007;10:508526. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Womens Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Womens Health Initiative randomized controlled trial. JAMA 2002;288:321333.
There is an increase in dementia in older women commenced on E+P/ERT. In the 65 to 79 years age group, ERT leads to an excess risk of 1.2 per 1,000 person-years and E+P to an excess risk of 2.3 per 1,000 person-years.
Gall Bladder Disease
The risk of gall bladder disease (and cholecystectomy) is increased with E+P.
2012 Medicine Today Pty Ltd. Initially published in Medicine Today April 2012;13(4):5961. Reprinted with permission.
CONCLUSION
HRT remains the most effective treatment for menopause symptoms, particularly the vasomotor symptoms and the atrophic changes. Maintaining and regularly updating ones knowledge about the menopause and HRT is paramount for each professional to be able to give information accurately.
About the Author

Dr Farrell is Head of the Menopause Unit, Monash Medical Centre, Southern Health, Melbourne, Victoria, Australia, and Past President of the Australasian Menopause Society. Declaration of interests: Dr Farrell has been on advisory committees and received educational and research grants from various pharmaceutical companies over the past 10 years but does not think these associations have influenced the content of this article.
REFERENCES
1. Sturdee DW, Pines A, on behalf of the International Menopause Society Writing Group. Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric 2011;14:302320. 2. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:14651477. 3. Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Womens Health Initiative randomised placebo-controlled trial. Lancet Oncol 2012;13:476486.
PAEDIATRICS PAEDIATRICS
II
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Managing Imaging Paediatric Headache Managing Headache in Children Brain in Tumours Children
M A McShane, MB BCh, MRCP(UK); S J Hughes, MBBS, MRCPCH Tang Phua Hwee, MBBS, FRCR, Diagnostic Radiology M A McShane, MB BCh, MRCP(UK); S JMMed Hughes, MBBS, MRCPCH
eadache is a common symptom in children. Recurrent or persistent headache is most commonly due to one of three main headache types: migraine (with and without aura), tension headache, and chronic daily headache. There are many good reviews of head-
ache and its treatment in the clinical journals. Headache including migraine affects up to 30% of the population and often begins in childhood. The classification system for headache introduced in 1998 by the International Headache Society has been updated and is widely used in research and clinical papers. Symptom overlap between the various headache syndromes is particularly common in children, making clear definition difficult in clinical practice. This paper will focus on the clinical management of headache in children including migraine and will not dwell on classification or diagnosis.
DIAGNOSIS
When considering the management of the child with headache, the importance of a detailed history and clinical examination cannot be overemphasized. Sufficient time is required to allow a good consultation in the child presenting with headache, particularly chronic headache. All parents are concerned that there may be serious underlying pathology. It is important not to miss serious pathology, and a recent paper published in the Archives of Diseases in Childhood (2010) provides a guideline to help identify those children who might have a tumour. Delay in making a diagnosis of brain tumour occurs in many children and adolescents, and particular features which might suggest a tumour include a change in headache symptom, persistent early morning headache, short but escalating history, physical symptoms such as altered gait or visual symptoms, cognitive decline, and hormonal disturbance (for example evidence of diabetes insipidus or growth failure). Headache in the very young (children less than 5 years) also needs to be
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managed with caution. In clinical practice, serious disorders such as tumours and conditions such as a Chiari 1 malformation are relatively rare causes of headache. If there is a typical history for migraine or tension headache and a thorough clinical examination is normal, then investigation is unlikely to be helpful. There is a place for organizing a scan in some patients for reassurance, but with increasing anxiety about the potential danger associated with X-radiation this should be with magnetic resonance imaging if done routinely. The clinician also needs to be aware that it is not uncommon for magnetic resonance imaging to reveal unexpected abnormalities often with no relevance to the presenting symptom. After taking a good history and undertaking a thorough examination, most patients can be reassured following discussion and formulation of a management plan. Time well spent at this first appointment may avoid unnecessary anxiety and repeated GP and hospital visits.
be warned that there may be some initial rebound. Sleep is important for all children, and poor sleep is a common association in those with chronic headache. Children and adolescents with migraines not only have a higher rate of sleep disturbance, such as insufficient sleep, daytime sleepiness and night waking, but in addition these problems tend to increase the frequency of headache. Advice aimed to improve sleep has the potential to reduce migraines. It is important to ask about bedtime; encourage a regular calm settling regime and recommend removal of distractions such as sound systems and televisions from the bedroom. Reducing caffeine intake is often advised although most children are not heavy tea and coffee drinkers. Parents need to be aware that many fizzy drinks contain caffeine and that it is best to drink plain tap water for thirst rather than sugary drinks. We often recommend that individuals with chronic headache increase fluid intake although evidence supporting this strategy is lacking. We feel that giving some responsibility to the parent and patient in terms of adapting their lifestyle can have a positive effect on symptoms possibly by giving them some control. Dietary factors may be important in some individuals, but restrictive diets in growing children are best avoided. Missing meals with resultant relatively low blood sugar seems to be a particular trigger in some individuals, and eating meals at regular intervals may be helpful for many patients. In those who have migraines triggered by sport, a small snack before activity can be beneficial. Stress has also been historically suggested as a cause for headache. While it may not necessarily be the cause, most of us would accept that stress contributes to headache severity and frequency. It may not be possible to recognize any particular stress in every patient, but enquiry is essential and measures to reduce stress encouraged. Psychological interventions are an emerging area of interest
HEADACHE MANAGEMENT (SIMPLE AND NON-PHARMACOLOGICAL MEASURES)

When we see a child with migraine or tension headache, we usually advise the family about non-medical interventions that might help the symptoms. There is good evidence that lifestyle issues impact upon headaches and migraines. Children who are obese have increased frequency and increased disability from attacks. There is also some evidence that weight loss in such patients may reduce the impact of migraines. Analgesic headache is now well recognized, and a self-perpetuating cycle of analgesic overuse can easily occur. Often simply stopping regular analgesic treatment can improve the headache symptoms particularly in those who report that the medicine is of no benefit, although the patient needs to
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in the treatment of migraine. There is some evidence that relaxation strategies are helpful for the individual in both preventing and treating migraine episodes. Biofeedback techniques and behavioural therapies such as cognitive behaviour therapy can have a positive effect on disabling chronic illness including chronic daily headache. A recent BMJ review (2011) notes that herbal remedies, mineral supplements and vitamins are sometimes used by patients who dislike drug treatment, and some have been shown to have efficacy including butterbur (Petasites hybridus ), magnesium and coenzyme Q10, but these are not without their potential side effects and uncertainty about dosage may have practical limitations for use particularly in children. We rarely advise these interventions, but some patients will research and use alternative medicine sometimes with useful effect. Feverfew was often used as a headache treatment, but lack of effect in a clinical trial has led to it becoming less popular. In the older adolescent patient with migraine with aura, the combined oral contraceptives is usually avoided, and in some individuals the pill can exacerbate headaches. Ergot derivatives are now rarely used in adult practice and never in children.
headache has resolved.
PHARMACOLOGICAL TREATMENT
Treatment is generally undertaken in a stepwise fashion, with the aim to minimize the requirement for medication where possible. It is important to balance the side effects of any treatments against the disabling effects of the migraine. This should always be done in consultation with child and family. If the migraine is infrequent and not severe, then simple measures should be employed. In children with migraine, we recommend that they try to sleep or at least rest after taking an analgesic until the
Acute Treatment of Migraine First-line treatments consist of routine analgesics: paracetamol, NSAIDS (non-steroidal anti-inflammatory drugs), and weak opiates such as codeine. There have been few studies assessing the effectiveness of simple analgesics in non-malignant chronic pain disorders including migraine. NSAIDs, such as ibuprofen, show statistical significance in the acute treatment of migraine, and all simple analgesics are most effective when taken early in the episode. Anti-emetics mentioned in the British National Formulary for Children (BNFc) include metoclopramide, domperidone, phenothiazines and antihistamines. Rectal preparations are available, but extrapyramidal side effects need to be mentioned. Regular and long-term use should be avoided. Formulations combining paracetamol, codeine and an anti-emetic are available and can be helpful for some patients, possibly owing to the anti-emetic action. Chronic analgesics use (abuse) can produce a persisting analgesic headache. The BMJ review paper suggests that in adults, simple analgesics should be used on no more than 15 days per month and migraine-specific acute drugs should be used no more than 10 days per month. The Lancet Neurology paediatric paper suggests that simple analgesia should be used on no more than 3 days per week and migraine-specific drugs no more than 6 days per month. If first-line analgesics are unsuccessful in migraine headaches, then triptans are now the recommended second-line acute treatment. The serotonin (5-HT) 1 agonists are not licensed for use in children, but the BNFc does give dosage recommendations for the drugs sumatriptan and zolmitriptan. Sumatriptan can be prescribed from 6 years and older and zolmitriptan from 12 years. Both need to
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be initiated by a specialist and should be avoided in children with cardiac disease, hypertension, and epilepsy. The 5-HT agonists can be administered orally or as melt-in-the-mouth tablets. In older children, they can be administered subcutaneously via an auto-injector or be given by the intranasal route. Triptans are generally well tolerated in the paediatric age group, but it is recommended that they be given as monotherapy. These drugs can interact with other medications and the serotonin syndrome, an atypical neuroleptic malignant syndrome, can be triggered. Caution is needed with this treatment particularly when on other prescribed medications. It is relatively rare for us to recommend triptans in children in our clinical practice. Recent evidence in adults has suggested efficacy for oxygen treatment in cluster headache, but fortunately this particularly distressing headache syndrome is rare in children. Pizotifen has antihistamine and anti-serotonin actions, but the evidence that it is an effective treatment for migraine is limited. Despite this lack of evidence, it is widely used. Adverse effects include increased appetite and drowsiness. We generally use pizotifen as first-line prophylactic treatment but giving this as a single dose at night to avoid daytime sedation. The BNFc gives doses from 5 years and older. It does have mild anticholinergic actions and can potentially cause problems such as urinary retention and worsening of glaucoma, but these are rarely a problem in children. Occasional behavioural disturbance is described. Pizotifen is not recommended for children with epilepsy. Propranolol is the most commonly used -blocker for migraine prophylaxis. It should not be given to patients with a history of asthma and bronchospasm. There is good evidence that -blockers are effective in migraine, but side effects can be troublesome including fatigue, cold extremities and poor sleep. The BNFc gives a dose schedule from 2 years and older, but we rarely use this drug in younger children and often find that it is not well tolerated in some older children. Postural hypotension may be a problem in some teenagers.
Aims of prophylactic treatment include reduction of attack frequency, severity and duration, as well as increased responsiveness to acute treatment during an attack
Headache and Migraine Prophylaxis There are no agreed guidelines on when prophylactic treatment should be used, but in our practice if significant headaches are occurring more than once weekly, daily prophylaxis should be considered. The BNFc suggests more than two attacks per month, but much depends on the response of the acute headaches to simple measures and the disability caused by the attacks. The decision to start a prophylactic drug requires careful discussion. Aims of prophylactic treatment include reduction of attack frequency, severity and duration, as well as increased responsiveness to acute treatment during an attack. The adverse effects of treatment also need to be discussed, and many parents will choose to avoid regular medication for their children because of anxieties about drug-related side effects. The BNFc mentions three prophylactic drug groups for use in children. These are pizotifen, -blockers, and anti-epileptics.
Peer Reviewed
Anti-epileptics drugs are useful in the management of migraine and other disorders with chronic pain. They are also useful for patients who fail to respond to other prophylactic agents. Clinical trials have shown efficacy for topiramate and sodium valproate. Carbamazepine may also be an effective treatment in some individuals and may have a better side effect profile. The BNFc recommends that these medications should be initiated and supervised by a specialist. A number of other treatments are available to treat children with chronic headache. Amitriptyline, an old antidepressant, is widely used in the management of chronic pain disorders in children and adults. We rarely use this in children younger than 12 years. Side effects include drowsiness and sometimes agitation. Anticholinergic side effects are described but rarely troublesome in children in the small doses used for this indication. Calcium channel blocker agents can be used to treat migraine, but their use is not licensed for this indication and we rarely use them other than for extremely rare conditions such as alternating hemiplegia. Botulinum toxin has recently obtained approval for use in chronic headache in both the UK and USA in adults. This treatment is not yet widely accepted as effective in the adult population and we would think indications for use in children will be very limited. There is also some emerging evidence in adults that certain nutrients such as coenzyme, riboflavin and magnesium may be helpful, but this has not been well studied in the paediatric population yet.
expectations when changing medications should occur with the patient and their family. Advice on the timing of cessation of prophylaxis is not well studied. We recommend reviewing the effectiveness of prophylactic treatment after 1 month and continuing treatment for 36 months. We do not recommend long-term treatment in children.
CONCLUSIONS
Headache is a common symptom in children and young people and requires careful clinical assessment. Once diagnosed, treatment should progress in a stepwise fashion, using simple lifestyle strategies and a range of medications, as necessary. Treatment goals and expectations should be agreed with patient and their family. Regular medications should be reviewed after a 1-month period, using diary recording for evidence of effectiveness. Longterm treatment in children should be avoided with breaks in treatment at 36 monthly intervals.
2011 Elsevier Ltd. Initially published in Paediatrics and Child Health 2011;21(11):518520.
Further Reading
Fenstermacher N, Levin M, Ward T. Pharmacological prevention of migraine. BMJ 2011;342:d583. doi:10.1136/bmj.d583. Hershey AD. Current approaches to the diagnosis and management of paediatric migraine. Lancet Neurol 2010;9:190204. Mack KJ. An approach to children with chronic daily headache. Dev Med Child Neurol 2006;48:9971000. Wilne S, Koller K, Collier J, Kennedy C, Grundy R, Walker D. The diagnosis of brain tumours in children: a guideline to assist healthcare professionals in the assessment of children who may have a brain tumour. Arch Dis Child 2010;95:534539.
Length of Treatment In children, it is often possible to stop prophylaxis after a period of time. It is recommended that throughout treatment, setting goals and reviewing
About the Authors
M A McShane is a Consultant Paediatric Neurologist at the Childrens Hospital at the John Radcliffe Hospital, Oxford, UK. Conflicts of interest: none declared. S J Hughes is a Consultant in Paediatric Neurodisability at the Royal Berkshire Hospital, Reading, UK. Conflicts of interest: none declared.
LL Chan, MBBS, MRCOG; WL Lau, MBBS, FRCOG, FHKAM (O&G); WC Leung, MBBS, MD, FRCOG, FHKAM (O&G), Cert RCOG (Maternal & Fetal Medicine)
INTRODUCTION
Gestational diabetes mellitus (GDM) is a controversial subject in obstetrics. It is defined by the National Diabetes Data Group in 1985 as carbohydrate intolerance of variable severity with onset or first recognition during pregnancy.1 The first case report of GDM appeared in 1824, which described a mother with thirst, polyuria and glycosuria and the death of a macrosomic infant from shoulder impaction. Historically, there has been a lot of controversy over most aspects of GDM, including screening, diagnosis, risks, treatment, and the relationship between GDM and type II diabetes mellitus. Recently, several major studies have substantially resolved these areas of controversy, eg, the Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) study,2 the Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS), and the Maternal-Fetal
3
Diagnosis and treatment of gestational diabetes can help reduce the risk of many adverse pregnancy outcomes due to this condition.
studied (eg, age, body build, ethnic origins). The United States reported an incidence of 38%, with a rising trend
5
(2529 years), 10.3% (3034 years), 21.7% (3539 years), and 31.9% ( 40 years), respectively, from the youngest to the oldest cohort ( P < 0.001). Another study 9 performed in a different university teaching hospital in Hong Kong, Prince of Wales Hospital, found that the prevalence of GDM was 14.2%. In our hospital, a regional hospital with around 6,000 deliveries per year, the incidences of GDM in 2008 and 2009 were 13.2% and 14.2%, respectively.
Medicine Units Network treatment of mild gestational diabetes (MFMUN-GDM) clin4
in more recent publications. The United Kingdom reported an incidence of 2%

6
ical trials, which will be discussed further in this article.
and Canada described 3.8%. 7 In Hong Kong, a study 8 performed in a university teaching hospital, Queen Mary Hospital, showed that of the 16,383 women incidence of GDM managed in the period 19982001, the prevalence of GDM increased from 1.3% ( 20 years), 2.5% (2024 years), 6.2%
INCIDENCE
The reported
varies with diagnostic criteria and characteristics of the population being
Figure 1. Flow chart showing guidelines as suggested by IADPSG10
At booking visit, all or high-risk women should have FG, HbA1c, RG tested
DM if FG 7.0 mmol/L, or HbA1c 6.5%, or RG 11.1 mmol/L
Normal
GDM if FG 5.1 mmol/L, but < 7.0 mmol/L
75-g OGTT at 2428 weeks
DM if FG 7.0 mmol/L
GDM if FG 5.1 mmol/L, or 1hG 10.0 mmol/L, or 2hG 8.5 mmol/L
1hG = 1-hour plasma glucose in 75-g oral glucose tolerance test; 2hG = 2-hour plasma glucose in 75-g oral glucose tolerance test; DM = diabetes mellitus; FG = fasting glucose; GDM = gestational diabetes mellitus; HbA1c = glycated haemoglobin A1c; IADPSG = The International Association of Diabetes and Pregnancy Study Groups; OGTT = oral glucose tolerance test; RG = random glucose.
SCREENING AND DIAGNOSIS

The diagnostic criteria of GDM were initially established more than 40 years ago, and these criteria were not designed to identify pregnant women at increased risk for adverse perinatal outcomes but rather women at higher risk for the development of diabetes after pregnancy. Following the publication of the HAPO study, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) established a new set of diagnostic guidelines (Figure 1). As more and more women suffer from
10
recommends screening women with risk factors at the booking visit by using random plasma glucose, fasting plasma glucose, or glycated haemoglobin A1c paired with diagnostic thresholds, according to the current guidelines for the diagnosis of pre-existing diabetes. Moreover, GDM can be diagnosed at the booking visit with a fasting plasma glucose between 5.1 mmol/L and 7.0 mmol/L, hence lowering the thresholds of GDM in most guidelines. They also recommend that all women who do not have diabetes should be screened at 2428 weeks gestation with the 75-g oral glucose tolerance test. In contrast
to the World Health Organization criteria which use an abnormal fasting or 2-hour plasma glucose for the diagnosis of diabetes, the IADPSG suggests that an abnormal 1-hour plasma glucose is adequate for the diagnosis. They also take into account the continuous association between maternal blood glucose concentrations and adverse perinatal outcomes as seen in HAPO. The agreed thresholds represent an odds ratio of 1.75 for birth weight, cord C-peptide, and fetal body weight being greater than the 90th percentile, relative to the odds of those outcomes at mean glucose values. Applying this system of testing and di-
diabetes before pregnancy, the IADPSG

agnostic criteria will probably double the incidence of GDM.

11
Table 1. Risks factors of gestational diabetesa
RISKS
The HAPO study2 was a 10-year, prospective, blinded, multicentre study, which enrolled 25,505 pregnant women. It aimed at studying the associations between the risks of adverse pregnancy outcomes and the degrees of maternal glucose intolerance less severe than overt diabetes. Exclusion criteria include fasting plasma glucose > 5.8 mmol/L, or the 2-hour plasma glucose 11.2 mmol/L, or a random plasma glucose 8.9 mmol/L. It showed an unambiguous, linear, positive association between maternal glycaemia and adverse pregnancy outcomes (eg, birth weight > 90th percentile, caesarean section, cord plasma C-peptide level reflective of fetal hyperinsulinemia, neonatal hypoglycaemia, excess neonatal adiposity, shoulder dystocia or birth injury, neonatal hyperbilirubinaemia,pre-eclampsia). 12,13 The risk factors and health risks of GDM are summarized in Tables 1 and 2.
Risk factors
Overweight Obesity Severe obesity Prior gestational diabetes Prior macrosomic infant Maternal age greater than 25 y Maternal age greater than 35 y Multiple gestation South East Asian Hispanic African American Polycystic ovarian syndrome Parent with diabetes Sibling with diabetes Periodontal disease Low maternal birth weight
a b
Odds ratio
2 3.7 7 23 3.3 1.4 2.3 2.2 7.6 2.4 1.8 2.9 3.2 7.1 2.6 1.9
b b b b
References
Torloni et al, Chu et al Torloni et al, Chu et al Torloni et al, Chu et al McGuire et al McGuire et al Cypryk et al Xiong et al Rauh-Hain et al Dornhorst et al Dooley et al Dooley et al Toulis et al Kim et al Kim et al Xiong et al Seghieri et al
Reprinted from Obstetrics and Gynecology Clinics of North America, 37(2), Pridjian et al, Update on gestational diabetes, 255267, 2010, with permission from Elsevier. Relative risk compared with white race.
Table 2. Health risks of gestational diabetesa Mother Birth trauma Increased caesarean delivery Pre-eclampsia/ Gestational hypertension Type 2 diabetes Metabolic syndrome Fetus Hyperinsulinaemia Cardiomyopathy Stillbirth Newborn Respiratory distress syndrome Hypoglycaemia Hypocalcaemia Child/Adult Obesity Type 2 diabetes Metabolic syndrome
TREATMENT
The ACHOIS3 and the MFMUN-GDM4 clinical trials demonstrated that diagnosis and treatment of GDM were worthwhile because these reduced the risk of many adverse pregnancy outcomes of GDM. In both studies which were double blind, women diagnosed with GDM in the late second and early third trimesters were randomized to two groups, ie, routine care or intervention. Intervention in both trials included
Large for gestational age/ macrosomia Birth trauma
Hypomagnesaemia Hyperviscosity Polycythaemia Hyperbilirubinaemia Cardiomyopathy
a Reprinted from Obstetrics and Gynecology Clinics of North America, 37(2), Pridjian et al, Update on gestational diabetes, 255267, 2010, with permission from Elsevier.
diet should be adjusted and individualized to meet the patients food choice, financial needs, culture, habits, weight gain, physical activity, and blood glucose goals. The Dietary Reference Intakes recommends no increase in calories for the first trimester but an additional 340 kcal/ day during the second trimester and 452 kcal/day during the third trimester. 17 In obese women with GDM, a 30% caloric restriction help to avoid ketonuria or an increase in free fatty acids,18 while improving glycaemic control. A more severe caloric restriction is not recommended. The National Institute for Clinical Excellence (NICE) guidelines19 in the UK recommend that women with GDM whose prepregnancy body mass index is above 27
Few studies have focused on the benefit of carbohydrates with a low glycaemic index.
kg/m2 should restrict caloric intake (to 25 kcal/kg/day or less) and engage in moderate exercise (of at least 30 minutes daily). The goal of fractionating food intake into three meals and two to three snacks in between meals is to distribute the glucose intake throughout the day in order to control the postprandial glucose, while at the same time maintaining a satisfactory nutritional intake. The evening snack decreases the night-time ketogenesis related to fasting. Generally, 4045% of the calories in the daily diet come from carbohydrates, but this must be individualized.20 One study showed that in women with GDM, carbohydrate restriction to < 42% led to fewer LGA infants, reduced rates of caesarean sections for macrosomia and cephalopelvic disproportion, and reduced need for insulin treatment, compared with a higher carbohydrate content (4550%).21
dietary modification, blood glucose monitoring, and, if needed, insulin treatment. In the ACHOIS trial, a composite measure
3
the MFMUN-GDM trial only. Rates of induction of labour and of admission to the neonatal unit were increased by treatment in the ACHOIS trial only. Generally, these two trials showed that identification and treatment of GDM with a standard approach improved pregnancy outcomes.
of serious perinatal complications (defined as one or more of death, shoulder dystocia, bone fracture, and nerve palsy) was reduced by diagnosis and intervention (adjusted odds ratio, 0.33; 95% confidence interval, CI, 0.140.75; P = 0.01). A similar composite measure in the MFMUN-GDM trial was also decreased but
4
DIETARY MODIFICATION
The scientific evidence for making nutritional recommendations for women with GDM is limited. Referral to nutritional counselling should ideally occur within 48 hours of the diagnosis of GDM. 15 The first meeting with a professional dietitian should be arranged within 1 week of the referral, and a total of three visits are suggested.
16
was not statistically significant (relative risk, 0.87; 97% CI, 0.721.07; P = 0.14). In both studies, rates of large-for-gestational-age (LGA)/macrosomia, pre-eclampsia and maternal pregnancy weight gain were reduced by intervention. Rates of shoulder dystocia and caesarean section were significantly decreased by treatment in
Throughout the pregnancy, the
Few studies have focused on the benefit of carbohydrates with a low glycaemic index (GI), which is a measure of how much each gram of available carbohydrate in the food increasing a persons blood glucose level following consumption of the food, relative to consumption of glucose. Food with carbohydrates that break down quickly during digestion and release glucose rapidly into the bloodstream tend to have a high GI, while food with carbohydrates that break down more slowly, releasing glucose more gradually into the bloodstream, tend to have a low GI. There have been no randomized studies with sufficient sample size to draw a conclusion on the benefits of carbohydrates with a low GI. Increased dietary fibre intake is traditionally recommended for women with GDM, as it may reduce the postprandial blood glucose. But no proof exists that extra dietary fibre intake is beneficial in these women.
blood glucose for 12 weeks, or if ultrasound shows possible fetal macrosomia (abdominal circumference above the 70th percentile) at diagnosis.
sions to neonatal units, or neonatal hypoglycaemia. Metformin belongs to the biguanide group. It inhibits hepatic gluconeogenesis and glucose absorption, and stimulates glucose uptake in peripheral tissues. The onset of action takes approximately 1 hour
When counselling patients, health carers can reassure them that the rates of congenital malformations with the use of oral hypoglycaemic agents and insulin do not differ
with the peak level at 24 hours after intake. Metformin does cross the placenta. Because it acts as an insulin sensitizer in peripheral tissues rather than as an insulin analogue, it is believed that fetal metabolism is less likely to be affected.25 The Metformin in Gestational Diabetes (MiG) trial26 of 751 women showed similar perinatal complications in both the metformin and insulin groups, with better acceptability in the metformin group; but subsequent insulin was indicated in 46.3% of women taking metformin. Long-term safety data on infants whose mothers were treated with glyburide or metformin are lacking. Early neonatal complications, such as hypoglycaemia, are not common and do not differ very much from those resulting from insulin therapy. When counselling patients, health carers can reassure them that the rates of congenital malformations with the use of oral hypoglycaemic agents and insulin do not differ. The maternal glucose control (fasting blood glucose and 2-hour postprandial) by oral hypoglycaemic agents and insulin is also comparable. Acarbose , an alpha glucosidase inhibitor, has been used less often. Preliminary studies showed that it was effective in decreasing postprandial hyperglycaemia in GDM, but its use has been limited by its side effects, like abdominal crampJPOG JUL/AUG 2012 173
Oral Hypoglycaemic Agents

Glyburide (or glibenclamide) is a second-generation sulfonylurea. It binds to receptors that are associated with the adenosine triphosphate-dependent potassium channels of pancreatic cells to increase insulin secretion and insulin sensitivity of peripheral tissues. The onset of action takes approximately 1 hour with the peak level at 4 hours after intake. Studies on the placental transfer of glyburide are contradictory. In vitro studies showed minimal placental transfer, but the fetal response to various dosages of glyburide is not completely known. 23 A meta-analysis by Moretti et al reported no differ24
PHARMACOTHERAPY
Drug treatment is necessary in 720% of women with GDM when, despite dietary modification, there is insufficient glucose control, high levels of fasting glucose, suboptimal weight gain (due to caloric restriction), or persistent hunger sensation. The Fifth International Workshop-Conference on Gestational Diabetes recommends the following blood glucose concentrations: fasting plasma glucose, 5.05.5 mmol/L; 1-hour postprandial plasma glucose, < 7.8 mmol/L; and 2-hour postprandial plasma glucose, < 6.77.1 mmol/L. guidelines
19 22
The NICE
ences between the insulin and glyburide groups with regard to birthweight, LGA/ macrosomia, gestation at delivery, admis-
recommend drug treatment
if diet and exercise cannot control the
ing.27 Further studies are needed to better evaluate the potential placental transfer of this drug, as small amounts of acarbose can be absorbed into the bloodstream.
lin analogue lispro has also been shown to be safe in observational studies. However, there is no safety data available on the long-acting insulin analogues detemir and glargine; both are prescribed offlabel. Therefore, long-acting human insulin should be used instead.
women with GDM is controversial because sufficient data are lacking to make a recommendation. Induction of labour in women with insulin-treated diabetes at 38 weeks gestation is intended to reduce the risk of stillbirth. One study30 failed to detect a benefit to expectant management beyond 38 weeks gestation, as the rate of caesarean delivery was not reduced but rather the rates of LGA infants and shoulder dystocia were increased. For uncomplicated GDM, no strong evidence exists to support earlier induction of labour, which was also confirmed by a Cochrane review of randomized trials on elective delivery in women with diabetes. 31 Prophylactic pre-labour caesarean section using estimated fetal weight by ultrasound has been proposed but is controversial. Recommendations concerning the lower estimated fetal weight thresholds for prophylactic caesarean section vary from 4,000 to 4,500 g. Both the American College of Obstetricians and Gynecologists and the Royal College of Obstetricians and Gynaecologists recommend prophylactic caesarean section if the estimated fetal weight is > 4,500 g. Another issue is the inaccuracy of ultrasound in estimating fetal weight, which leads to an increase in unnecessary caesarean deliveries and, therefore, caesarean-associated maternal and fetal morbidities, and additional health-care costs.
Insulin
Traditionally, insulin has been regarded as the standard treatment for diabetes, especially when diet and exercise fail to control the maternal blood glucose and there is no risk of placental transfer of insulin to the fetus. Insulin requirements are not constant throughout the day: it is low at night with a sharp rise at dawn, followed by a gradual decrease during the rest of the day. Women in the first trimester are at risk of hypoglycaemic events because of emesis, and blood glucose levels should be closely monitored with appropriate adjustment of insulin. After the second trimester, insulin requirements rise. During labour, shortacting insulin should be used to achieve optimal glucose levels of between 4 and 8 mmol/L and to prevent neonatal hypoglycaemia. After delivery, glycaemic control must be relaxed to prevent maternal hypoglycaemia, especially in breastfeeding women. Insulin therapy should be stopped in women who have not taken insulin before pregnancy, while those women who are taking insulin for pre-existing diabetes should resume their pre-pregnant insulin dosages. There are two types of insulin: human insulin and insulin analogue. The short-acting insulin analogue aspart has been shown to be safe in pregnancy in a randomized trial 28 and has been registered for this indication. The short-acting insuJPOG JUL/AUG 2012 174
ANTENATAL MANAGEMENT
Once GDM is diagnosed, visits to health carers or dietitians by the pregnant women should be made at least every 12 weeks and more frequently if complications occur. There is no consensus on the frequency and timing of antenatal surveillance tests in women with GDM. It is crucial to manage women, who do not comply with advice, require drugs, have macrosomic or growth-restricted fetuses, or have other obstetric complications, as though they had pre-existing diabetes and to begin close antenatal monitoring (eg, the NICE guidelines suggest anomaly scan, echo19
cardiography, growth scan at 28, 32 and 36 weeks gestation, tests of fetal wellbeing after 38 weeks gestation). History review, blood pressure measurement, and urine albumin testing to diagnose preeclampsia are also essential at every visit. In an attempt to prevent macrosomia and to guide the treatment, a randomized trial compared ultrasound performed at
29
32 weeks gestation with ultrasound at both 28 and 32 weeks gestation. The rate of macrosomia was significantly higher in the group assessed only at 32 weeks (71.1% vs 33.3%; P < 0.005). The mode and timing of delivery of
POSTPARTUM MANAGEMENT
Approximately 50% of women with GDM will develop type 2 diabetes within 5 to
10 years. 32 An Italian study 33 showed that GDM is a stronger predictor of later metabolic syndrome after adjustments for pre-pregnancy body mass index and age. In a large 4- to 23-year follow-up study in Denmark, 68% of the 481 women with previously diagnosed GDM had impaired glucose regulation, 59% had elevated fasting serum insulin, 54% had central obesity, 28% had hypertension, and 35% had dyslipidemia, presenting with higher triglycerides levels and lower high-density lipoprotein cholesterol levels compared with the control group.34 Diagnostic testing for diabetes is appropriate 6 weeks after delivery. It is
unclear whether a traditional 2-hour 75-g oral glucose tolerance test or fasting plasma glucose test may be more useful at this time. The frequency of follow-up blood glucose tests for early detection of impaired glucose tolerance or diabetes varies from annual to triennial. Advice on postpartum weight loss, which may help reduce the occurrence of type 2 diabetes mellitus, includes breastfeeding, dietary modification, and exercising for at least 150 minutes every week.35
mation of results from randomized intervention trials, the IADPSG guidelines are unlikely to be widely adopted worldwide. Without a uniform diagnosis, research on risks and management is difficult. Women with GDM should be treated with dietary modification, appropriate exercise, and drugs, if necessary. Oral hypoglycaemic agents (eg, glyburide, metformin) are as useful as but not better than insulin alone in terms of early pregnancy outcomes.
CONCLUSION
Without further cost analyses and confir-
About the Authors

Dr Chan is a resident trainee, and Dr Lau and Dr Leung are consultants, practicing in the Department of Obstetrics and Gynaecology, Kwong Wah Hospital, Kowloon, Hong Kong SAR.
References
1. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28:10391057. 2. Metzger BE, Lowe LP, Dyer AR, et al; HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358:19912002. 3. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS; Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005;352:24772486. 4. Landon MB, Spong CY, Thom E, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med 2009;361:13391348. 5. Coustan DR. Gestational diabetes. In: Diabetes in America. 2nd ed. NIH Publication No. 951468. Bethesda, MD: National Diabetes Data Group, National Institutes of Health, National Institutes of Diabetes and Digestive and Kidney Diseases; 1995:703717. 6. Scott DA, Loveman E, McIntyre L, Waugh N. Screening for gestational diabetes: a systematic review and economic evaluation. Health Technol Assess 2002;6:1161. 7. Griffin ME, Coffey M, Johnson H, et al. Universal vs. risk factor-based screening for gestational diabetes mellitus: detection rates, gestation at diagnosis and outcome. Diabet Med 2000;17:26 32. 8. Lao TT, Ho LF, Chan BC, Leung WC. Maternal age and prevalence of gestational diabetes mellitus. Diabetes Care 2006;29:948949. 9. Ko GTC, Tam WH, Chan JCN, Rogers M. Prevalence of gestational diabetes mellitus in Hong Kong based on the 1998 WHO criteria. Diabet Med 2002;19:80. 10. International Association of Diabetes and Pregnancy Study Groups. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33:676682. 11. Moses RG. New consensus criteria for GDM: problem solved or Pandoras box? Diabetes Care 2010;33:690691. 12. HAPO Study Cooperative Research Group. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study: associations with neonatal anthropometrics. Diabetes 2009;58:453459. 13. HAPO Study Cooperative Research Group. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: preeclampsia. Am J Obstet Gynecol 2010;202:255.e1255.e7. 14. Pridjian G, Benjamin TD. Update on gestational diabetes. Obstet Gynecol Clin North Am 2010;37:255267. 15. American Diabetes Association. Nutrition recommendations and interventions for Diabetes. A position statement of the American Diabetes Association. Diabetes Care 2008;31(Supp1):S61 S78. 16. Reader D, Splett P, Gunderson EP; Diabetes Care and Education Dietetic Practice Group. Impact of gestational diabetes mellitus nutrition practice guidelines implemented by registered dietitians on pregnancy outcomes. J Am Diet Assoc 2006;106:14261433. 17. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC: National Academies Press; 2002. 18. Knopp RH, Magee MS, Raisys V, Benedetti T, Bonet B. Hypocaloric diets and ketogenesis in the management of obese gestational diabetic women. J Am Coll Nutr 1991;10:649667. 19. National Collaborating Centre for Womens and Childrens Health. Diabetes in Pregnancy: management of diabetes and its complications from preconception to the postnatal period. London: RCOG Press; 2008 March. 20. Reader D, Sipe M. Key components of care for women with gestational diabetes. Diabetes Spectrum 2001;14:188191. 21. Major CA, Henry MJ, De Veciana M, Morgan MA. The effects of carbohydrate restriction in patients with diet controlled gestational diabetes. Obstet Gynecol 1998;91:600604. 22. Metzger BE, Buchanan TA, Coustan DR. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 2007;30 Suppl 2:S251S260. 23. Elliott BD, Langer O, Schenker S, Johnson RF. Insignificant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol 1991;165:807812. 24. Moretti E, Rezvani M, Koren G. Safety of glyburide for gestational diabetes: a meta-analysis of pregnancy outcomes. Ann Pharmacother 2008;42:483490. 25. Brown FM, Wyckoff J, Rowan JA, Jovanovic L, Sacks DA, Briggs GG. Metformin in pregnancy: its time has not yet come. Diabetes Care 2006;29:485486. 26. Rowan JA, Hague WM, Gao W, Batting MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:20032015. 27. Garcia-Bournissen F, Feig DS & Koren G. Maternal-fetal transport of hypoglycaemic drugs. Clin Pharmacokinet 2003;42:303313. 28. Hod M, Damm P, Kaaja R, et al; Insulin Aspart Pregnancy Study Group. Fetal and perinatal outcomes in type 1 diabetes pregnancy: a randomized study comparing insulin aspart with human insulin in 322 subjects. Am J Obstet Gynecol 2008;198:186.e1186.e7. 29. Rossi G, Osomigliana E, Moschetta M, Bottani B, Barbieri M, Vignali M. Adequate timing of fetal ultrasound to guide metabolic therapy in mild gestational diabetes mellitus: results from a randomized study. Acta Obstet Gynecol Scand 2000;79:649654. 30. Kjos SL, Henry OA, Montoro M, Buchanan TA, Mestman JH. Insulin-requiring diabetes in pregnancy: a randomized trial of active induction of labor and expectant management. Am J Obstet Gynecol 1993;169:611615. 31. Boulvain M, Stan C, Irion O. Elective delivery in diabetic pregnant women. Cochrane Database Syst Rev 2001;(2):CD001997. 32. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002;25:1862 1868. 33. Bo S, Monge L, Macchetta C, Menato G, et al. Prior gestational hyperglycemia: a long-term predictor of the metabolic syndrome. J Endocrinol Invest 2004;27:629635. 34. Lauenborg J, Mathiesen E, Hansen T, et al. The prevalence of the metabolic syndrome in a Danish population of women with previous gestational diabetes mellitus is three-fold higher than in the general population. J Clin Endocrinol Metab 2005;90:40044010. 35. Knowler WC, Barrett-Connor E, Fowler SE, et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393403.
CME Questions
This continuing medical education service is brought to you by the Medical Progress Institute, an institute dedicated to CME learning. Read the article Gestational Diabetes and answer the following questions. This JPOG article has been accredited for CME by the Hong Kong College of Obstetricians and Gynaecologists.
CME Article
Answer True or False to the questions below.
True 1. Gestational diabetes mellitus (GDM) can present in the first trimester. 2. The incidence of GDM in Hong Kong is 25%. 3. The selected thresholds in the International Association of Diabetes and Pregnancy Study Groups guidelines represent an odds ratio of 1.75 for birth weight and cord C-peptide, relative to the odds of those outcomes at mean glucose values. 4. Rates of shoulder dystocia and caesarean section were significantly reduced by treatment in the ACHOIS and MFMUN-GDM trials. 5. In obese women with GDM, there should be a 40% restriction of caloric intake. 6. Metformin is registered and approved for use in pregnancy. 7. Glyburide can cause fetal hyperinsulinaemia. 8. The National Institute for Clinical Excellence recommends fortnightly growth scans in women with GDM from 32 weeks gestation. 9. The Royal College of Obstetricians and Gynaecologists recommends prophylactic caesarean section if the estimated fetal weight is greater than 4,000 g. 10. The 75-g oral glucose tolerance test is the recommended test in the postnatal period of women with GDM.
Name in BLOCK CAPITALS: Signature: Date:
Please mail your completed answer sheet back to: The Secretariat Hong Kong College of Obstetricians & Gynaecologists Room 805, Hong Kong Academy of Medicine Jockey Club Building 99 Wong Chuk Hang Road, Aberdeen, Hong Kong
False
CME Answers for JPOG Jan/Feb 2012

of Pregnancies With Previous Caesarean Section
Answers
1 2 3 4 5 6 7 8 9 10 T F F T T T T T T F
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JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY

J UL/ AUG 2 0 1 2 Vol. 38 No. 4

Enquiries and Correspondence

Marisa Lam Greg Town

Managing Editor Associate Editor

Agnes Chieng, Sam Shum

Edwin Yu, Ho Wai Hung, Steven Cheung

Minty Kwan Jenny Lim

JPOG JUL/AUG 2012 ii

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JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY

J UL/ AUG 2 0 1 2 Vol. 38 No. 4

Continuing Medical Education

169 Gestational Diabetes

Lisa Low, Illustrator

JPOG JUL/AUG 2012 iii

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PPI use by postmenopausal women increas-

Screening and cervical cancer mortality

JPOG JUL/AUG 2012 133

replacement for smoking cessation during pregnancy. Ibid: 846847 (editorial).

Results of modern paediatric burn care

JPOG JUL/AUG 2012 134

Chlorhexidine to the umbilical cord in developing countries

Moderate or late preterm birth and health outcomes

JPOG JUL/AUG 2012 135

Oral amoxicillin for severe early childhood pneumonia in rural Pakistan

questionnaire was based on previous similar sur-

Paediatricians influence parental febrile behavior

JPOG JUL/AUG 2012 136

PATHOGENESIS AND AETIOLOGY

Figure 1. Typical well-demarcated, salmon-pink patches with silvery scale.

Figure 2. Psoriasis in the concha of the ear.

Figure 3. Napkin psoriasis.

munological basis for disease.

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Figure 4. Differential diagnosis. a. Discoid eczema. b. Tinea corporis. c. Pityriasis rosea.

JPOG JUL/AUG 2012 139

Figure 5. Pustular psoriasis requires hospitalization.

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Table 1. Criteria for psoriatic arthritis proposed by Vasey and Espinoza

Criterion I: Psoriatic skin or nail involvement Criterion II: Peripheral pattern

Criterion III: Central pattern

Table 2. Possible regimes

psoriasis and then maintaining with minimal or no therapy (Table 2).

All treatments are considered to be suppressive rather than curative

JPOG JUL/AUG 2012 142

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Emollients provide prompt relief of scaling or irritated skin.

PA ED IATRICS Peer Reviewed