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INDONESIA ISSN 2411-0183JUL/AUG 2017VOL. 43 NO. 4JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGYYOUR PARTNER IN PAEDIATRIC, OBSTETRIC & GYNAECOLOGY PRACTICEGYNAECOLOGY Colposcopy and Cervical Intraepithelial NeoplasiaOBSTETRICS Analgesia in Labour and DeliveryCME ARTICLE Bleeding in Early PregnancyJUL/AUG 2017 VOL. 43 NO. 4Editorial BoardBoard Director, PaediatricsProfessor Pik-To CheungAssociate Professor, Department of Paediatrics and Adolescent MedicineThe University of Hong Kong, Hong KongBoard Director, Obstetrics and GynaecologyProfessor Pak-Chung HoDirector, Centre of Reproductive MedicineThe University of Hong Kong - Shenzhen Hospital, ChinaCONFERENCEAmerican Society of Clinical Oncology (ASCO) 2017 Annual Meeting, June 2-6, Chicago, Illinois, US133? Pregnancy still possible after breast cancer? Chronic disease incidence declines over time inProfessor Biran AffandiUniversity of Indonesia, IndonesiaProfessor HextanYuen-Sheung NganThe University of Hong Kong, Hong KongProfessor Kenneth KwekKK Women’s and Children’s Hospital, SingaporeProfessor Kok Hian TanKK Women’s and Children’s Hospital, SingaporeProfessor Dato’Dr. Ravindran Jegasothy Dean Faculty of Medicine, MAHSA University, MalaysiaAssociate Professor Daisy ChanSingapore General Hospital, SingaporeAssociate Professor RaymondHang Wun LiThe University of Hong Kong, Hong KongAdjunct Associate ProfessorNg Kee ChongDivision of Medicine & Academic Clinical Program (Paediatrics), c/o KK Women’s and Children’s Hospital, SingaporeProfessor Seng-Hock Quak National University of Singapore, SingaporeAdjunct Associate ProfessorTan Ah MoyKK Women’s and Children’s Hospital, SingaporeDr. Catherine Lynn Silao University of the Philippines Manila, PhilippinesDwiana Ocviyanti, MD, PhDUniversity of Indonesia, IndonesiaDr. Karen Kar-Loen Chan The University of Hong Kong, Hong KongDr. Kwok-Yin LeungThe University of Hong Kong, Hong KongDr. Mary Anne Chiong University of the Philippines Manila, PhilippinesDr. Wing-Cheong Leung Kwong Wah Hospital, Hong Kong, Hong Kongchildhood cancer survivorsJOURNAL WATCH134? Autism spectrum disorder: Updated guidelines for GPs? Triponderal mass index superior to BMI for evaluating body fat during adolescence? Isolated maternal hypothyroxaemiain third trimester linked to pre-eclampsia135? Low rate of DRMs, vertical transmission of HIV-1 among women treated with Option B+136? High prevalence of lower genital tract infection among women in Beijing, China? Traumatic life events affect cellular ageing in women of reproductive ageMIMSGEMPOWERING HEALTHCARE COMMUNITIESFind your calling MIMS Career is a job portal linking organisations and companies tohealthcare professionals.Seek your next opportunity.ejob.idaJ? job.my:'job.ph job.sg·---. ./JUL/AUG 2017 VOL. 43 NO. 4CEO Yasunobu SakaiManaging Editor Elvira Manzano Medical Editor Elaine Soliven Designer Sam ShumProduction Edwin Yu, Ho Wai Hung, Steven Cheung, Agnes ChiengCirculation Christine Chok Accounting Manager Minty Kwan Advertising Coordinator Pannica GohPublished by:MIMS (Hong Kong) Limited27th Floor, OTB Building, 160 Gloucester Road, Wan Chai, Hong KongTel: (852) 2559 5888 | Email: enquiry@Enquiries and CorrespondenceREVIEW ARTICLEGYNAECOLOGY137Colposcopy and Cervical IntraepithelialNeoplasiaCervical cancer is caused by certain types of human papillomavirus (HPV) and is preceded by a long precancerous stage of cervical intraepithelial neoplasia (CIN). Cervical cancer can be prevented by successful introduction of HPVimmunization programme and screeningusing HPV testing, cytology, and colposcopy.ChinaYang XuanTel: (86 21) 6157 3888Email: @Hong Kong Jacqueline Cheung Tel: (852) 2559 5888Email: enquiry.hk@IndiaMonica BhatiaTel: (91 80) 2349 4644Email: enquiry.in@KoreaChoe Eun YoungTel: (82 2) 3019 9350Email: inquiry@kimsonline.co.krIndonesiaFatmawati, Fransiska Simamora, Ruth Theresia, Sari WiyantiTel: (62 21) 729 2662Email: enquiry.id@MalaysiaTiffany Collar, Sumitra Pakry, Sharon Ong, Wong Wen Dee Tel: (60 3) 7623 8000Email: enquiry.my@PhilippinesKims Pagsuyuin, Rowena BelgicaTel: (63 2) 886 0333Email: enquiry.ph@SingaporeJosephine Cheong, Ronald HoTel: (65) 6290 7400Email: enquiry.sg@ThailandNawiya WitayarithipakornTel: (66 2) 741 5354Email: enquiry.th@VietnamNguyen Thi Lan Huong, Nguyen Thi My Dung Tel: (84 8) 3829 7923Email: enquiry.vn@Aslam Shiraz, Tarang MajmudarOBSTETRICS149Analgesia in Labour and DeliveryPain due to labour requires speci?c management which falls outsidethe basic principles of acute pain management and it is important for practitioners who look after these patients to understand what can be offered. This review considers the basicprinciples of each of these techniques using common clinical scenarios. The type of analgesia given will determine where labourtakes place and this will be re?ected in each case.PUBLISHER: MIMS Journal of Paediatrics, Obstetrics & Gynaecology (JPOG) is published 6 times a year by MIMS Pte Ltd. CIRCULATION: JPOG is a controlled circulation for medical practitioners in South East Asia. It is also available on subscription to members of allied professions. SUBSCRIPTION: The price per annum is US$42 (surface mail, students US$21) and US$48 (overseas airmail, students US$24); back issues US$8 per copy. EDITORIAL MATTER published herein has been prepared by professional editorial staff. Views expressed are not necessarily those of MIMS Pte Ltd. Although great care has been taken in compiling and checking the information given in this publication to ensure that it is accurate, the authors, the publisher and their servants or agents shall not be responsible or in any way liable for the continued currency of the information or for any errors, omissions or inaccuracies in this publication whether arising from negligence or otherwise howsoever, or for any consequences arising therefrom. The inclusion or exclusion of any product does not mean that the publisher advocates or rejects its use either generally or in any particular field or fields. COPYRIGHT: ? 2017 MIMS Pte Ltd. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, in any language, without written consent of copyright owner. Permission to reprint must be obtained from the publisher. 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Apoteker? Perawat? Dokter SpesialisLainnya (Sebutkan) Formulir dan bukti pembayaran dikirim/fax ke:PT Medidata IndonesiaGedung Aquarius Lt. 1,Jl. Sultan Iskandar Muda No. 7, Pondok IndahJakarta Selatan 12240Tel. (021) 729 2662 (Hunting), Fax: (021) 729 3539Email: enquiry.id@ivMIMS JPOG JUL/AUG 2017REVIEW ARTICLEPAEDIATRICS160Acute Kidney Injury in Paediatric Critical CareIncidence of acute kidney injury (AKI) is gradually increasing in children admitted to critical care units partly because of increased awareness of this entity. Inthis review, we have attempted to outline the current de?nitions used for AKI, presence of AKI in various critical careconditions (bone marrow transplant, liver, sepsis, cardiac, and primary renal conditions leading to glomerulonephritis), and outline the basic management.Rupesh Raina, Abigail Chauvin, Akash DeepJUL/AUG 2017 VOL. 43 NO. 4MIMS JPOG welcomes papers in the following categories:Review ArticlesComprehensive reviews providing the latest clinical informationon all aspects of the management of medical conditions affecting children and women.Case StudiesInteresting cases seen in general practice and their management.Pictorial MedicineVignettes of illustrated cases with clinical photographs.For more information, please refer to the Instructions for Authors on our website , or contact:The EditorMIMS Pte Ltd438A Alexandra RoadAlexandra Technopark# 04-01/02Singapore 119967Tel: (65) 6290 7400Fax: (65) 6290 7401E-mail: enquiry@CONTINUING MEDICAL EDUCATION169Bleeding in Early Pregnancy2 SKPVaginal bleeding commonly occurs in pregnancy. More than 20% of pregnant women with successful deliveries experienced vaginal bleeding during the antenatal course.1 Two of the most important differential diagnoses for patients presenting with bleeding in early pregnancy are miscarriage and ectopic pregnancy.Pun Ting Chung, Yung Shuk Fei Sofie, Wan Hei Lok TiffanyThe Cover: Acute Kidney Injury in Paediatric Critical Care? 2017 MIMS Pte LtdPeggy Tio, DesignerMIMS8EMPOWERING HEALTHCARE COMMUNITIESAsia's one-stop resource for drug prescribinginformationactlonsFind comprehensive medical reference information online with MIMS Drug Reference. It comprises disease guidelines, brand and manufacturer's resources, clinical and general news updates,CMEtools and industry conference reports.Access online at or via the MIMS mobile app.CONFERENCE COVERAGEMIMS JPOG JUL/AUG 2017133American Society of Clinical Oncology (ASCO) 2017 Annual Meeting, June 2-6, Chicago, Illinois, US– Elaine Soliven reportsPregnancy still possible after breast cancerWomen with a history of estrogen recep- tor (ER)-positive breast cancer (BC) who subsequently got pregnant appears to have similar disease-free survival (DFS) as those who did not get pregnant, ac- cording to a study.“Our findings confirm that preg- nancy after breast cancer should not be discouraged, even for women with ER-positive cancer,” said lead study au- thor Dr Matteo Lambertini from the In- stitut Jules Bordet in Brussels, Belgium.The multicentre, retrospective co- hort study consisted of 1,207 women,57 percent of whom had a history of ER-positive BC. Of these, 333 women became pregnant after BC and were matched with 874 nonpregnant women. [ASCO 2017, abstract LBA10066]Researchers found no significant difference in DFS between pregnant and nonpregnant women who had ER-positive BC (hazard ratio [HR],0.94, 95 percent confidence interval [CI], 0.70–1.26; p=0.68) or ER-neg- ative BC (HR, 0.75, 95 percent CI,0.53–1.06; p=0.10) at 12.5 years from conception (in the matched pregnant women).There was also no difference in overall survival (OS) between pregnant and nonpregnant women who had ER-positive BC (HR, 0.84, 95 percent CI,0.60–1.18; p=0.32).However, among those with ER-negative BC, pregnant women had a significantly increased OS than non- pregnant women (HR, 0.57, 95 percent CI, 0.36–0.90; p=0.01).“It’s possible that pregnancy could be a protective factor for pa-tients with ER-negative breast cancer, through either immune system mech- anisms or hormonal mechanisms, but we need more research into this,” said Lambertini.Dr Matteo Lambertini, et al, American Society of Clinical Oncology (ASCO) 2017 Annual Meeting, June 2-6, Chicago, Illinois, US [abstract LBA10066].Chronic disease incidence declines over timein childhood cancer survivorsThe incidence of chronic disease among childhood cancer survivors has decreased over the past decades and it is likely due to advances in treatment, according to a study in the US.“Our analysis marks the first com- prehensive assessment of changes in the rates of chronic health complications over time in a large group of cancer sur- vivors,” said lead author Dr Todd Gibson from St. Jude Children’s Research Hos- pital in Memphis, Tennessee, US.Researchers gathered data from the CCSS* cohort and analysed23,601 childhood cancer survivors (median age 28 years). The incidence of severe (grade 3), life-threatening or disabling (grade 4), or fatal (grade 5) health conditions reduced within 15 years of childhood cancer diagno- sis at 12.7 percent in the 1970s, 10.1 percent in the 1980s, and 8.8 percent in the 1990s. [ASCO 2017, abstract LBA10500]After adjusting for age and gender, a significant risk reduction was noted in childhood cancer survivors who had Wilms tumour (hazard ratio [HR], 0.57), Hodgkin lymphoma (HR, 0.75), astrocy-toma (HR, 0.77), acute lymphoblastic leukaemia (HR, 0.86), and nonHodgkin lymphoma (HR, 0.79).The decline in severe health con- ditions in the 1990s was predominantly due to decreased occurrence of endo- crine conditions (4.0 percent vs 1.6 per- cent, HR, 0.66, 95 percent confidence interval [CI], 0.59–0.73) and subsequent malignant neoplasms (2.4 percent vs1.6 percent, HR, 0.85, 95 percent CI,0.76–0.96) compared with those diag- nosed in the 1970s.In addition, there was also a sig- nificant reduction in the incidence of gastrointestinal and neurological con- ditions (HR, 0.80, 95 percent CI, 0.66–0.97 and HR, 0.77, 95 percent CI, 0.65–0.91, respectively). However, there was no reduction in cardiac or pulmonary conditions.The cardiac findings were con- sidered ‘surprising’, noted Gibson, given that deaths from cardiovascular disease declined among survivors in recent decades. “This is a reminder that survivors continue to have an in- creased risk for serious health prob- lems compared to the general popula- tion and need to be followed closely,” he said.Overall, the findings suggest that survivors who were diagnosed and treated in more modern treatment eras are doing better, said Gibson. “Not only are more children being cured, but they also have lower risk for developing se- rious health problems due to cancer treatment later in life.”*CCSS: Childhood Cancer Survivor StudyDr Todd Gibson, et al, American Society of Clinical Oncolo- gy (ASCO) 2017 Annual Meeting, June 2-6, Chicago, Illinois, US [abstract LBA10500].134 MIMS JPOG JUL/AUG 2017PPaediatricsAutism spectrum disorder: Updated guidelinesfor GPsAutism spectrum disorder (ASD) affects approximately one in 100 children world- wide and GPs are often the first and most important contact for parents of children with ASD. In particular, GPs play a key role in recognizing early signs of ASD, referring children for specialist assess- ment, supporting the child and their family, reviewing specialist prescribed medication, and coordinating specialist support. It is important, therefore, that they be knowledgeable about the early signs of ASD and understand the impor- tance of early intervention.ASD is currently defined by the fifth edition of the Diagnostic and StatisticalManual of Mental Disorders (DSM-5) of the American Psychiatric Association. Although it is a lifelong condition, ASD emerges in early infancy and can be relia- bly diagnosed as early as age 2. Possible red flags include signs of communica- tion, social, and behavioural disturbanc- es at 12–24 months of age. In particular, children who do not babble, coo, or ges- ture by pointing, waving, or grasping by age of 12 months, who do not say single words by 16 months, and who do not say any two-word phrases without prompting by age of 24 months should be referred for specialist assessment. Any child with a loss of language or social skills at any age should also be referred, since dete- rioration in behaviour might indicate an acute illness in a person with ASD such as an ear infection. Comorbid anxiety, at- tention deficit hyperactivity disorder, and depression are also common. However, it is important to remember that children with ASD can present in a number of dif- ferent ways depending on their current symptoms, cognitive ability, and educa- tional and life experiences.Brereton AV and Tonge B., Autism spectrum disorder: An up- date for GPs. Medicine Today 2017;18:42-48.Triponderal mass index superior to BMI for evaluating body fat during adolescenceTriponderal mass index (TMI) is a su- perior index of body fat compared with body mass index (BMI) in adolescents, according to a recent study.Using the US National Health andNutrition Examination Survey (1999–2006), researchers analysed cross-sec- tional dual-energy X-ray absorptiometry and anthropometric data from 2,285 non-Hispanic white participants aged8–29 years to determine changes inbody fat levels, body proportions, and the scaling relationships among body mass, height, and percent body fat. Sta- bility with age, accuracy in estimating percent body fat, and accuracy in clas- sifying adolescents as overweight vs nor- mal weight were used to determine the superior index.The standard weight-to-height re- gression was not valid for finding the op- timal body fat index since percent body fat varied with both age and height during adolescence. Unlike BMI which increases dramatically with age, necessitating the development of age-specific percentiles, TMI was stable between ages 8 and 17. TMI was also better at estimating percent body fat than BMI (R2=0.64 vs 0.38 for boys and R2=0.72 vs 0.66 for girls), and misclassified adolescents as overweight rather than normal weight less often than BMI z-scores (8.4 percent vs 19.4 percent misclassified, respectively; p<0.001). In addition, the index performed as well as updated BMI percentiles derived from the same data set (TMI 8.4 percent vs BMI8.0 percent; p=0.62), but was much sim- pler to use since TMI does not require percentile calculations.Peterson CM, et al, Tri-ponderal mass index vs body mass in- dex in estimating body fat during adolescence. JAMA Pediatr2017.doi:10.1001/jamapediatrics.2017.0460.OObstetricsIsolated maternal hypothyroxaemia in thirdtrimester linked to pre-eclampsiaResearchers in China have shown that isolated maternal hypothyroxaemia (IMH)JOURNAL WATCH PEER REVIEWED MIMS JPOG JUL/AUG 2017135detected during the third trimester of pregnancy is strongly correlated with pre-eclampsia in the first large-scale in- vestigation to undertake long-term moni- toring of free thyroxin (FT4) levels in Chi- nese mothers with hypothyroxaemia.In the study, first (week 9–12) and third (week 32–36) trimester serum sam- ples were collected from 6,031 mothers (aged 21–43 years) for analyses of thy- roid function. All of the women had sin- gleton pregnancies, were Han Chinese, had no history of thyropathy or autoim- mune disease, no goiters, were thyroid peroxidase antibody (TPOAb)-negative, and did not use medicines that would af- fect thyroid hormone levels. In addition, all had TSH levels within the reference intervals during the first and third trimes- ters of pregnancy. Women were moni- tored for adverse pregnancy outcomes such as gestational diabetes mellitus (GDM), pregnancy-induced hyperten- sion, and pre-eclampsia.The researchers found that women who were older and those who had a higher pre-pregnancy body mass index were more likely to experience hypothy- roidism. Although pregnancy-induced hypertension was not significantly corre- lated with FT4, GDM, and pre-eclampsia were inversely correlated with maternal FT4 levels during early and late preg- nancy, respectively. In particular, women with IMH during the third trimester had an increased risk of developing pre-ec- lampsia.Zhang Y, et al, Maternal low thyroxin levels are associated with adverse pregnancy outcomes in a Chinese population. PLoS ONE 2-17;12:e0178100.Low rate of DRMs, vertical transmission of HIV-1 among women treated with Option B+The 2012 WHO guidelines recommend the initiation of lifelong antiretroviral combination therapy for all pregnant HIV-1 positive women in resource-limited settings regardless of their CD4 count or clinical stage to prevent mother-to- child transmission of HIV-1 (Option B+). There has been some concern that such programmes may encourage the devel- opment of drug resistance mutations (DRMs), but a recent study has shown that the risk of drug resistance is low.A total of 124 HIV-1 positive preg- nant women in Fort Portal, Uganda, were enrolled in the study. Blood samples were collected at their first visit to the an- tenatal clinic before initiating Option B+ as well as at 6 weeks and 6, 12, and 18 months postpartum. Viral load was deter- mined by real-time RT-PCR and analyses were also made of vertical transmission. A total of 49 women (39.5 percent) were also included in a DRM analysis. Virolog-ical failure was defined as >1,000 copiesHIV-1 RNA/mL.At 1-year postpartum, three wom- en were found to have virological fail- ure, and seven were affected by the18-month time point. No vertical trans- mission of HIV-1 was noted among the49 mother-infant pairs included in the DRM analysis. However, three wom- en had developed DRMs, and two had dual-class resistance against all recom- mended first-line drugs.The researchers suggested that their findings of a low DRM selection rate support the continued adoption of the Option B+ for preventing mother-to-child transmission of HIV-1.Machnowska P, et al, Decreased emergence of HIV-1 drug re- sistance mutations in a cohort of Ugandan women initiating option B+ for PMTCT. PLoS ONE 2017;12:e0178297136136 MIMSMIMSJPOGJPOGJUL/AUGJUL/AUG20172017 JOURNAL WATCH PEER REVIEWEDGGynaecologyHigh prevalence of lower genital tract infection among women in Beijing, ChinaThe prevalence of lower genital tract in- fection (LGTI) in Beijing is high and that of co-infection is of a magnitude that war- rants attention by public health services, according to a recent study.There has been a notable increase in the incidence of LGTI in recent years, which is of concern since the link be- tween high-risk human papillomavirus (HR-HPV) and other sexually transmitted diseases remains unclear and untreat- ed LGTI such as Chlamydia trachomatis may cause pelvic inflammatory disease, which has been linked to miscarriages, preterm birth, ectopic pregnancy, and tu- bal factor infertility.Researchers in China analysed data from 1,218 married women aged 20±70 years who were resident in Beijing for at least 6 months and underwent routine annual gynaecologic health checks be- tween March and October 2014. Cervical secretions and vaginal swab specimens were tested for C. trachomatis, Neisseria gonorrhoeae, Ureaplasma urealyticum, yeast, clue cells, and HR-HPV. The wom- en also completed a structured question- naire that provided data on demographic status, reproductive health history, sexu- al behaviour, symptoms of genital tract infection, use of vaginal medications, and use of contraceptive methods.Laboratory results were available for 1,195 women. Forty-seven percent had LGTI, most commonly U. urealyti- cum (35.5 percent), bacterial vaginosis(10.5 percent), and yeast infection (3.7 percent). HR-HPV (7 percent) was de- tected and significantly correlated with abnormal cervical cytology (p<0.0001). Moreover, the risk of HR-HPV infection was significantly increased by the pres- ence of bacterial vaginosis (odds ra- tio, 3.0, 95 percent confidence interval,1.7±5.4; p<0.0001).Zhang D, et al, Epidemiological investigation of the relationship between common lower genital tract infections and high-risk human papillomavirus infections among women in Beijing, China. PLoS ONE 2017;12:e0178033..Traumatic life events affect cellular ageing in women of reproductive ageWomen of reproductive age who suffer a traumatic life event such as the loss of a child have a faster pace of cellular ageing than those who do not, and this appears to be affected by maternal hy- pothalamic-pituitary-adrenal axis (HPAA) activity, say Canada-based researchers.They tested the hypothesis that psychological challenges increase the age-related pace of biological ageing by measuring telomere attrition in a cohort of Kaqchikel Mayan women living in a population with a high frequency of child mortality. The women are part of an on- going longitudinal study of the relation- ship between naturally occurring stress and women’s reproductive function. Ge- netic variability was reduced since the women were all Kaqchikel Mayan with at least five generations of traceable ances- tors. Moreover, they had similar lifestyles in terms of diet, physical activity, edu- cation, and socioeconomic status, and none smoked.Telomere length was quantified by qPCR of buccal specimens collected from 55 women in 2013, and HPAA activ- ity was assessed by quantifying cortisollevels in first morning urinary specimens collected every other day for 7 weeks during that same year. Child mortality data were collected in 2000 and 2013.Only women who experienced child mortality were found to have shorter telomere lengths with increasing age (p=0.015). Notably, shorter telomere length was linked to higher than average basal cortisol levels (p=0.007) as well as greater variations in basal cortisol lev- els over time (p=0.053). Nonparametric bootstrapping analyses indicated that HPAA activity mediated the effect of child mortality on telomere length.The researchers suggested that more large-scale longitudinal studies are required to confirm their findings.Barha CK, et al, Child mortality, hypothalamic-pituitary-ad- renal axis activity and cellular aging in mothers. PLoS One2017;12:e0177869.NUTRICIANUDUOA,._AllergyCareRangkaian lengkap produk untuk pencegahan dan penanganan alergi susu sapiFormula untuk menurunkan risiko alergiFormula penanganan alergi susu sapiRisiko AlergiAlergi BeratAlergi Sedang - RinganAllerpre 1-2 Neocate Pepti JuniorSoya 1-4Q Formula dengan Q Formula Q Formula Q Formula100% proteindengan 100% dengan 100% dengan isolatwhey asam amino protein whey protein terhidrolisanon alergenik terhidrolisa kedelaiparsialftft Cepat danekstensifft TelahTeruji klinis . efektifft Dapat digunakanmengurang1mengatasiditoleransi oleh>20 tahunrisiko alergi gejala ASS97% anak oleh anak di hingga usia 5 dalam 3-14dengan alergi Indonesia??tahun' hari2 3 susu sapiringan-sedang4NUTRICIARangkaian lengkap produk untukbayi prematur, underweight & Growth FalteringNUDUCIA??PretermCareGrowthFalteringFormula Bayi Prematur & BBLR di rumah sakitFormula Bayi Prematur & BBLR pasca rawatFormula BayiUnderweightFormula Anak dalamKondisi SakitPremature Post Discharge lnfatrini NutrinidrinkQQ Energi Q Energi Q Energi Energi150 kkal/100ml80 kkal/100 ml 74 kkal/100 ml 101 kkal/lOOmluntuk pemenuhanuntuk formulauntuk formulauntuk bayi dengan asupan nutrisi anak perawatan di setelah gangguanberusia 1-12 tahun rumah sakit dipulangkan dari pertumbuhandalam kondisi sakitJAt Sesuaidenganrumah sakitJAt Terbukti klinis JAt Terbukti klinisketentuanJAt Dilengkapi dengan mendukung meningkatkan beratESPGHAN untuk lcFOS/scGOS (1:9) tumbuh kejar badan anak dalamformula bayi untuk tanpa kelebihan28 hari pemakaian3prematur meningkatkanbeban cairan2mikrobiota saluran cerna1Colposcopy and CervicalIntraepithelial NeoplasiaAslam Shiraz MA (Cantab) MB BChir (Cantab); Tarang Majmudar MBBS MD (Mumbai, India) FRCOGCervical cancer is caused by certain types of human papillomavirus (HPV) and is preceded by a long precancerous stage of cervical intraepithelial neoplasia (CIN). Cervical cancer can be prevented by successful introduction of HPV immunization programme and screening using HPV testing, cytology, and colposcopy. In the last decade and going forward, signi?cant progress has been made in cervical screening methodologies, which are likely to further reduce the disease burden of cervical cancer and morbidity associated with CIN. We now have a better understanding of the natural history of HPV infection and progression of CIN. Three vaccines are currently available and immunization programmes are well established in developed and developing countries. Cytology screening is currently done using liquid-based cytology with additional HPV testing for triage and test of cure. This will be replaced in the UK, in the near future, with primary HPV screening. New adjunctive technologies to colposcopy are now available that improve the sensitivity of colposcopy and havethe potential to reduce the morbidity associated with CIN.INTRODUCTIONCervical cancer is one of the common-est malignancies affecting young wom- en. In 2012, the International AgencyREVIEWFigure 1.Transforming versus productive infection. Immunohistochemistry staining using p16 (red) and E4 (green). The p16 is a surrogate marker of E7 expression. The image demonstrates that as low-grade lesion transforms into high-grade lesion (CIN 1–3), p16 staining is dramatically increased while E4 staining (associated with a productive infection) diminishes in intensity. (Courtesy of Professor John Doorbar, HPV Lab, University of Cambridge)for Research in Cancer (IARC) reported 528,000 new cervical cancer cases together with 266,000 deaths worldwide from cervical cancer. Nearly85% of the disease burden and the deaths there- of occurred in the developing world. This wide disparity is attributed mostly to the availability and coverage of well-established screening pro- grammes in the developed world. In the UK, since the cervical screening programme was introduced in 1988, there has been a marked decrease in cer- vical cancer incidence from 16.2/100,000 female population to 8.3/100,000 over 20 years. In stark contrast, countries such as Uganda and Estonia have reported an increase in the incidence of cer- vical cancer.WHAT IS CERVICAL INTRAEPITHELIAL NEOPLASIA?CIN is the precursor of invasive squamous cell cancer of the cervix. It occurs due to the dys- plastic growth of squamous cells on the surface of the cervix. Similar to other intraepithelial neo- plasia, CIN is not malignant and completely cur- able. In the majority of cases, CIN would either remain stable or regress as the immune system eliminates the HPV virus that causes it.AETIOLOGY AND RISK FACTORSHPV is the single biggest risk factor in the devel- opment of cervical cancer or precancer CIN. To date, there exist over a 100 HPV types. Of these, HPV types 16 and 18 are responsible for 66% of cervical cancers. HPV types 31, 33, 45, 52, and58 account for a further 15% of cervical cancers. HPV-16 DNA would be the most common in squa- mous carcinomas, while HPV-18 DNA would be more common in adenocarcinomas.Other risk factors for CIN exist, however these risks seem to be associated with a higher risk of HPV contraction and persistence rather than being aetiological agents. These risk fac- tors include early onset of sexual activity, multiple partners, sexually transmitted infections such as herpes simplex/chlamydia, smoking, low socio- economic class, and HIV.NATURAL HISTORY OF HPV INFECTION AND CINThe process by which HPV induces neoplasia is now better understood. Most cases of cervical HPV infection occur in young adults aged 18–28. The infection in itself is transient and most women (90%) would clear it within 6–14 months. However, a minority of women (10%) end up with viral persistence. This is described as a latent infection. The virus stays within the basal layer of the epithelium without integrating with the host DNA. In women with a latent infection, cy- tology and colposcopy will be negative. About10–20% of these latent infections will progress to a productive infection. In a productive infection (Figure 1), the virus reaches the superficial and intermediate layers of the epithelium. The viral genome integrates with the host DNA and there is expression of viral E1, E2, and E4 proteins, which causes replication of viral DNA. In the superficial layer of the epithelium, there is ex- pression of viral LI and L2 proteins leading to formation of the complete virion particle, which is shed and can infect adjacent cells. However, a productive infection will not lead to cervical can- cer in the majority of women. On cytology andTable 1. CIN Classification SystemsDysplasia terminologyOriginal CIN terminologyModified CIN terminologyThe Bethesda system (SIL) terminology(1991)NormalNormalNormalWithin normal limits benign cellular changes (infection or repair) ASCUS/AGUSAtypiaKoilocytic atypia, flat condyloma, without epithelial changesLow-grade CINLSILMild dysplasia or mild dyskaryosisCIN 1Low-grade CINLSILModerate dysplasia or moderate dyskaryosisCIN 2High-grade CINHSILSevere dysplasia or severe dyskaryosisCIN 3High-grade CINHSILCarcinoma in situCIN 3High-grade CINHSILInvasive carcinomaInvasive carcinomaInvasive carcinomaInvasive carcinomaCIN: Cervical intraepithelial neoplasia; LSIL: Low-grade squamous intraepithelial lesion; HSIL: High-grade squamous intraepithelial lesion; ASCUS: Atypical squamous cells of undetermined significance; AGUS: Atypical glandular cells of undetermined significance.(Reproduced with permission from IARC WHO Colposcopy Manual, Chapter 2)colposcopy, these women will generally have features of low-grade CIN. In 10% of women with a productive infection and very rarely in women with a latent infection, the viral DNA integrates with the host DNA and causes expression of viral E6 and E7 proteins which leads to the loss of cell cycle control, mitosis, and uncontrolled cell proliferation resulting in a transforming infection (Figure 1), which can subsequently lead to inva- sive cervical cancer. On cytology, histology, and colposcopy, these women will generally have features of high-grade CIN.CLASSIFICATION OF CIN (Table 1) Traditionally, CIN has been graded as CIN 1, 2, and 3 depending on the degree of differentiation of the cervical squamous epithelium. The diag- nosis relies on features of nuclear abnormalities, cell stratification, and the proportion of the thick- ness of the undifferentiated epithelium.CIN 1 demonstrates undifferentiated cells in the basal layer of the epithelium. It has only min- imal nuclear anomalies and sparse mitotic bod-ies. CIN 2 leads to dysplastic changes occurring in the lower half of the epithelium together with more numerous nuclear anomalies and mitotic bodies. Finally, in CIN 3, there is complete dis- array with nuclear anomalies and mitotic bod- ies through the full thickness of the epithelium (Figure 2).The NHS Cervical Screening Programme (NHSCSP) recommends the use of the three-tier terminology for the histological reporting of CIN (CIN1, CIN2, and CIN3). The advantages of the three-tier system are that it allowed direct corre- lation with the cytological grades of dyskaryosis and that it ensured continuity in the recording, transfer, and storage of coded data to existing lo- cal, regional, and national databases. Collection and analysis of this data is necessary to evalu- ate the effectiveness of the cervical screening programme.However, when providing guidance for pa- tient management, the three-tier grading system is of limited value. Patient management is based on a two-tier grading system of low-grade CINL1E4L1ETE4Viral DNAETCIN progressionETE4Viral DNAETViral DNACIN1CIN2CIN3CaCxLSILHSILCervical cancerDEREGULATION OF E7 LEVELS IN BASAL & PARABASAL LAYERSINTEGRATION AND/OR SECONDARY GENETIC CHANGESFigure 2. Progression of CIN from a low-grade lesion to cancer. Adjacent to this are the HPV proteins that would be expressed for such a change. (Courtesy of Professor John Doorbar, HPV Lab, University of Cambridge)(CIN1) and high-grade CIN (CIN2 and CIN3) ab- normalities.The WHO histological classification of 2014 has modified the classification of intraepithelial lesions into two grades and currently classifies them into low-grade CIN, which would corre- spond to CIN1 or LSIL and high-grade CIN cor- responding to CIN2, CIN3, or HSIL.Histological grading using traditional HE staining is complicated by – 1) other conditions such as inflammation and atrophy which mimic changes of CIN and alter the histological inter- pretation; and 2) the high inter-observer variabil- ity in grading CIN.With a clearer understanding of the HPV viral gene expression producing different states of HPV infection (latent, productive and trans- forming infection), it is now possible to use bi- omarkers in differentiating between low-grade (productive infection) and high-grade lesions (transforming infection).Various biomarkers can be used to iden- tify E6 and E7 gene expression (p16) as well as cellular proliferation (Ki-67, MCM, and E4). Histological staining with these biomarkers hasshown to improve the sensitivity in the diagno- sis of transforming infection over traditional HE staining. This would be particularly useful in the medical management of younger women with a histological diagnosis of CIN2 on traditional HE staining. Immunostaining has the potential to differentiate between productive and transform- ing infection and thereby help to decide which of these young women need treating.CGINThis article would not be complete without men- tioning cervical glandular intraepithelial neopla- sia (CGIN). CGIN is the precursor lesion of a cervical adenocarcinoma. HPV 18 plays a major aetiological role. However, unlike CIN, the natu- ral history of CGIN is not well understood. The NHSCSP classification system divides glandu- lar lesions into two broad categories ie, border- line changes and glandular neoplasia.However, the disease burden related toCGIN is on the rise. Today, approximately 20–30% of cervical cancers are classed as adeno- carcinomas. These tumours may have a more aggressive course and thus a poorer prognosis.HPV vaccination is likely to prevent over 70% of all cervical cancers as well as other HPV-mediated cancers such as anal or oral cancer.CGIN can also be prevented and treat- ed through HPV immunization and screening technologies.PREVENTION Lifestyle factorsLifestyle modification through use of protect- ed intercourse with condoms and cessation of smoking can have an impact on prevention of HPV infection and CIN. There is some evi- dence to suggest that smoking may produce local immunologic changes that facilitate in- fection and possible persistence of HPV infec- tion. Although male condoms are effective in reducing the transmission of HPV, they may not offer full protection as HPV can infect ar- eas that are not covered by a condom. There is some evidence to suggest that condom use may promote HPV clearance and CIN1 regres- sion in women who use condoms consistently for 3 months.HPV vaccinationHPV vaccination was introduced in the UK in Sep- tember 2008. By 2014, 2.3 million girls have been vaccinated in England with coverage of 85% of the eligible population. At present, there are three forms of vaccines available depending on which types of HPV virus they are protective against.‘Cervarix’ offers protection against HPV 16 and18, ‘Gardasil’ against four types – HPV 6, 11, 16, and 18 and ‘Gardasil 9’ against nine types – HPV6, 11, 16, 18, 31, 33, 45, 52, and 58. Both Cervar- ix and Gardasil provide almost 100% protection against HPV types 16 and 18 related cervical dis- ease, and with Gardasil 9 providing an additional97% protection against HPV types 31, 33, 45, 52, and 58 related cervical disease.Overall, vaccination is likely to prevent over70% of all cervical cancers as well as prevent- ing other HPV-mediated cancers such as anal or oral cancer. In light of this, the WHO has recom- mended that HPV vaccination to be part of the routine schedule of vaccination for girls betweenHIV-positive women should have annual cytology and if possible at the outset of the diagnosis, a colposcopy if resources permit.the ages of 9 and 13. At present, the vaccine is thought to be efficacious for at least 8–9 years after the initial regimen and women are still rec- ommended to have cervical cancer screening.ScreeningScreening for CIN is done by cytological as- sessment of cells obtained from the surface of the cervix. This dates back to methods that originated with Papanicolaou in the 1940s where cells were scraped from the cervix using a spatula and smears prepared on slides for as- sessment. Cytological screening has changed since 2004 in the UK from the original method using smears prepared from a cervical scrape to liquid-based cytology (LBC). There are many advantages to this method including semi-au- tomation and uniform spread of the epitheli- al cells, meaning they are easier to read and reduce the number of unsatisfactory samples. It also allows for the concomitant use for HPV DNA testing.Since 2013, screening is performed in Eng- land and Northern Ireland using LBC with con- comitant use of HPV testing for ‘Triage’ in wom- en with borderline and low-grade dyskaryosis and also as ‘Test of Cure’ following treatment for CIN and CGIN. Wales and Scotland use HPV testing with LBC for ‘Test of Cure’.Future of screeningIn the near future, it is expected that the current method of screening using LBC and HPV testing will be replaced by primary HPV screening.Following a review of results from the Eng- lish HPV primary screening pilot sites and inter- national evidence, the UK National Screening Committee recommended in January 2016 that HPV primary screening should be adopted by the screening programme. The Public Health Minister subsequently approved this in July2016. It is intended that the implementation of HPV primary screening will be a phased ap- proach and could take until 2019.The key reasons for this approval were:? HPV-based primary screening provides a60–70% greater protection against cervical carcinomas compared with LBC.? HPV testing is more sensitive and has a very high negative predictive value.? It is cost-effective as it will save more lives and reduce costs through extension of screeningintervals.ColposcopyColposcopy is the basis of secondary screen- ing in the UK. Hans Hinselmann first described this method in 1925 as a way of examining the cervix using a low-powered microscopy. It also allows obtaining of biopsies and treating cervical intraepithelial lesions at the time of examination.The basis of colposcopy is to visualize un- der magnification of the transformation zone and its reaction to 3–5% acetic acid or Lugol’s iodine. The transformation zone is the area where CIN develops and is defined anatomi- cally as the area in between the original squa- mocolumnar junction (SCJ) which is laid down in foetal life and the new SCJ, which is formed when the hormonal changes of puberty lead to eversion of the cervix and exposure of the co- lumnar epithelium to the acidic pH of the vagi- na, inducing metaplastic change into the squa- mous epithelium.Colposcopy is only deemed as a satisfac- tory screening method if the entire SCJ and the upper limit of the lesion are visualized. Only if both these factors are realized will appropriate diagnosis, counselling, and treatment occur.Colposcopic abnormalities are graded according to the appearance of acetowhite change, iodine uptake, and vascular patterns (eg, mosaicism, punctuation, and atypical ves- sels). Thus, assessments are subjective and prone to inter-observer variability. This variation is markedly reduced for high-grade (HG) le- sions and the PPV of a colposcopic impression of CIN3 was noted to be 78% in a systematic review.Figure 3. (a) Colposcopic view of the cervix 60 seconds after acetic acid staining;and (b) Same cervix as in Figure 3a with DySIS map overlaid.FUTURE OF COLPOSCOPYThere are multiple adjuncts that are now available that improve the sensitivity and/or specificity of colposcopy alone. These include devices such as DySIS and Niris Imaging System.DySIS is a digital video colposcope that also uses dynamic spectral imaging to evalu- ate the ‘whitening’ effect of acetic acid on the epithelium (Figures 3a and 3b). It produces adepth of 1.6 mm. The Niris system has a lower sensitivity for identifying CIN2 + lesions (86.5% vs 99%) but a similar specificity (63.6% vs 61%) when compared to conventional colposcopy.The National Institute for Health and Care Excellence (NICE) has recommended that Dy- SIS is clinically and cost-effective option com- pared with standard colposcopy. There is cur- rently insufficient evidence to justify Niris as acost-effective adjunct to colposcopy.NICE has recommended that DySIS is clinically and cost-effective option compared with standard colposcopy.quantitative measurement of the rate, extent, and duration of the acetowhitening. The dynam- ic map (DySIS map) produced can be overlaid on a colour image of the tissue to help the cli- nician determine the presence and grade of the lesion. DySIS has been demonstrated to have a sensitivity of 79.6% compared with 51.9% for colposcopy alone; however the specificity was lower at 62.6% vs 81.7%.The Niris Imaging System uses optical co- herence tomography as an adjunct to a standard colposcope. It uses near-infrared light to pro- duce real-time, high-resolution, and cross-sec- tional imaging of tissue microstructure up to aReferral criteria for colposcopyCurrently, the indications for colposcopy referral are defined by the NHSCSP and include:? One cervical sample showing borderline/low- grade dyskaryosis changes in squamous cells that are high-risk HPV positive.? One cervical sample showing low-grade dys- karyosis changes in squamous cells with un- reliable HPV testing.? One cervical sample showing high-grade (moderate or severe) dyskaryosis (does not require reflex HPV test).? One cervical sample showing possible invasion.? Three consecutive inadequate cervical screening samples.? One cervical sample showing borderline changes in endocervical cells.? One cervical sample showing glandular neo- plasia.? Any grade of dyskaryosis following treatment for CIN before return to routine recall.? Three abnormal cervical samples of any grade over a 10-year period.? Suspicious symptoms and an abnormal look- ing cervix.Colposcopy and management of CIN The guiding principles for the management of CIN following colposcopy assessment are as follows:? If low-grade (LG) CIN is suspected/ confirmed on biopsy, consider expectant monitoring. Over 50% of LG CIN lesions will regress over 22 months. Treatment may beconsidered if low-grade abnormalities per- sist for more than 2 years and there are con- cerns that patient may not be compliant to surveillance.? If HG CIN is suspected/confirmed on biopsy, then consider treatment.? If there is discrepancy between cytology, histology, and colposcopy findings, consid- er MDT review and plan management as per consensus opinion.Conservative management of CIN2Approximately 3% of the screened UK popula- tion will have high-grade (moderate or severe) dyskaryosis at cytology. Of these, most wom- en with histologically high-grade lesions (CIN2 or greater) will be recommended for treatment. However, there are small proportion of young women who have CIN2 lesions who may have not completed their families and may not accept the risks of treatment (described below). Such women may instead opt to have regular cyto- logical and colposcopic surveillance with treat- ment if there is evidence of disease progression. There are studies which demonstrate that not all cases of CIN2 progress to high-grade or in- vasive disease. It is also possible that some of these cases were in fact LG CIN and would have regressed anyway. Immunostaining can differen- tiate between transforming and productive infec- tion, and can potentially help in the decision to conservatively manage CIN2 in selected cases. Until immunostaining is available in routine prac- tice, conservative management of CIN2 should be done in agreement with the patient after re- view at an MDT.Management of cervical glandular abnormalitiesAtypical glandular cytology is suggestive of CGIN or cervical adenocarcinoma. Women with borderline changes in endocervical cells on cytology and who tested positive for HR-HPV should undergo colposcopy and an appropri- ate cervical biopsy. In these women, CGIN isidentified in up to 10% of cases, HG CIN in up to 33%, and invasive disease in up to 22% of cases. In comparison, women referred with cy- tology results reported as ‘possible glandular neoplasia of endocervical type’ have high prev- alence of CGIN, invasive endocervical adeno- carcinoma, and HG CIN.Colposcopy lacks sensitivity for the diag- nosis of glandular lesions but allows anatomical assessment for mapping the biopsy. Directed punch biopsy has low sensitivity in the diagno- sis of CGIN and cannot reliably exclude invasion. Therefore, if CGIN/invasive disease is suspected, an excisional biopsy which includes the endocer- vical canal is required.CIN in pregnancy and menopause Pregnant women who have an indication for colposcopy should undergo the procedure. The aim is to exclude invasive disease and post- pone any intervention to the postnatal period once this is excluded. An experienced colpos- copist should undertake colposcopy in a preg- nant woman as vascular and hormonal changes of pregnancy can lead to an over diagnosis and treatment. If invasive disease is suspected, a biopsy should be taken in the form of a loop or wedge biopsy (punch biopsy is not reliable). There is a risk of haemorrhage and miscarriage/ preterm labour, and therefore the procedure should occur in a setting that allows appropri- ate management of these complications.Menopausal women have lower incidence of abnormal cytology and HPV positivity. HPV triage has a higher positive predictive value for menopausal women. In this age group, vaginal bleeding should be managed via the postmenopausal bleeding pathway and smear/ colposcopy is not the right investigation in this context.CIN in immunosuppressed patients Women who are immunosuppressed or at risk of immunosuppression are managed as higher risk patients. There is good evidence that womenguidelines. There is no evidence that these wom- en are at higher risk of CIN. Women with SLE on long-term chemotherapy may be at increased risk of CIN. However, at present, the evidence isinsufficient for increased surveillance.CIN can be treated by ablative and excisional techniques.who have renal failure and require dialysis or re- nal transplantation have an increased incidence of abnormal cytology (15%). However, even with this increased risk, the uptake of cervical screen- ing is poor among transplant recipients. Thus, it is essential that their cervical cancer screening status be reviewed at their annual transplant review.All women who are HIV positive should have annual cytology and if possible at the out- set of the diagnosis, a colposcopy if resources permit. There is an increased prevalence of CIN lesions (3% vs 20–40%) in HIV infected patients. Furthermore, regression of these lesions is rare and there is a higher rate of treatment failure with one study demonstrating an 87% recur- rence rate in HIV patients.Women who are on cytotoxic chemotherapy for either nongenital cancers or rheumatological conditions should have screening as per nationalTreatment of CINTreatment of CIN is done using a variety of meth- ods. All methods should be efficient in eradicat- ing the intraepithelial lesions and minimizing any adverse effects, particularly on future pregnan- cies, as the majority of women undergoing treat- ment are of reproductive age.CIN can be treated by ablative and excision- al techniques. Both have a cure rate of >90% and there is no difference between the two tech- niques when it comes to treating and eradicat- ing CIN. Both methods aim to remove the trans- formation zone and lesion. All techniques used should remove tissue to a depth of 7–10 mm so as to ensure eradication of CIN that may involve the gland crypt.The technique used for treatment of CIN relies on patient-specific factors such as the pa- tient’s age, colposcopic appearance, depth and size of the lesion, type of transformation zone, and fertility status.CGIN in contrast to CIN should be man- aged using excisional techniques only. Patients with CGIN can be managed with a conservative excision provided adequate surveillance is pos- sible. However, if the excision margins are in- volved, a further excision should be undertaken and if this fails, consideration must be given to a hysterectomy.Most UK centres use excisional techniques for treatment of CIN and in particular, the LLETZ procedure. Excisional techniques allow the as- sessment of the excision margins and exclude in- vasion. It is quick, easy to learn, low in cost, and well tolerated by patients. Excisional techniques are indicated in cases of suspected invasion, glan- dular involvement, repeat treatments, and if any discrepancy exists between cytology, colposcopy, and histology. The disadvantage is with the use ofexcisional techniques in a ‘see & treat’ approach which may lead to overtreatment in some women.Ablative techniques destroy the cervical ep- ithelium. Hence, accurate pretreatment punch biopsy samples are required to exclude invasion prior to ablative treatment. Punch biopsies, how- ever, have a low sensitivity in excluding invasion and CGIN. Therefore, ablative treatments should only be used in selective cases where the trans- formation zone and lesion are completely visible, there is no discrepancy between cytology, col- poscopy, and histology, and there is no sugges- tion of glandular or invasive lesions.Ablative techniquesVarious ablative techniques are available such as cryocautery, cold coagulation, laser ablation, and diathermy ablation. Cryocautery is the com- monest ablative technique used.Cryocautery: This technique ablates cer- vical tissue by freezing and using probes of various shapes and sizes. Cryocautery is rec- ommended to be used only for the treatment of low-grade CIN as the rate of clearance of HG CIN is poor. A freeze-thaw-freeze technique is advo- cated with a freeze cycle of 60 seconds, as this increases the cure rate. This technique is cheap to perform and therefore is widely used in the developing world.Excisional techniquesVarious excisional techniques are available. These include LLETZ/loop biopsy, NETZ/SWETZ (needle/straight wire excision of transformation zone), cold knife conization, laser conization, and hysterectomy.LLETZ/loop biopsy (large loop excision of transformation zone): This is the most widely practiced technique in the UK and usually per- formed under local anaesthetic. It is safe, cheap, and easy to use, and the thermal artefact damage to the specimen margins is minimal if performed appropriately.Cold knife conization: Rarely used today in the UK but is still being used in some Europeancountries. It requires a general anaesthetic. It is useful in cases of suspected invasion and glandu- lar disease as the lack of diathermy avoids ther- mal artefact and allows accurate assessment of excision margins. There is, however, an increased risk of haemorrhage and an adverse impact on reproductive outcomes.Hysterectomy: Still retains a place in man- agement of CIN in patients who have coexisting gynaecological problems such as menorrhagia or fibroids. It is also used to treat lesions where future fertility is not required, repeat excisions are not possible due to altered cervical anatomy as a result of previous excisions, and cytological and colposcopic surveillance is not possible due to persistently inadequate LBC or unsatisfactory colposcopy. It is important to ensure complete ex- cision of the cervix to reduce the risk of residual CIN and VAIN.Treatment complicationsComplications of CIN treatment are rare and more likely with excisional techniques. Early complications include primary haemorrhage (<1%), which is easily controlled using diather- my or Monsel’s solution. In difficult cases, su- tures can be placed. Secondary haemorrhage usually occurs approximately 2–3 weeks after the procedure. It is usually due to infection and is effectively treated with a course of broad-spec- trum antibiotics.Late complications: Excisional treatment is associated with adverse reproductive outcome in subsequent pregnancy in a small proportion of women and this is directly related to the depth of excision, volume of cervical tissue removed, and technique/type of excision.Excisional treatment of CIN does not af- fect the ability to conceive or have an impact in the first trimester of pregnancy. There is some limited evidence that it may increase the risk of second trimester miscarriages from 0.4%–1.6%.Excisional treatment can increase the risk of preterm birth if depth of excision is more that 10 mm. The absolute risk increases from 7% in thePractice Points?Cervical HPV infection is common but only a small proportion (1–2%) of women develops a transforming infection which leads to HG CIN and invasive cancer.?HPV infection and CIN is preventable by vaccination and screening.?Three vaccines are available. Gardasil 9 is a nonavalent vaccine which has a 100% protection against HPV 16 and 18 and further 97% protection against HPV 31, 33, 45, 52, and 58.?LBC with HPV testing for triage has been successfully introduced in parts of the UK since 2013. This will be replaced by primary HPV screening in the near future.?Colposcopy will continue to remain a secondary screening test in the foreseeable future. Adjunctive technologies such as DySIS and Niris are available that increase the sensitivity and/or specificity of colposcopy.?Management of patients referred for colposcopy should be done as per guidance in the NHSCSP Document 20.?Excisional treatment for CIN is associated with an increased risk of second trimester miscarriages and preterm births if excision depth is more than 10 mm. It is important to appropriately counsel women who have not completed their family about these risks.?Immunostaining can help to identify transforming infection with greater accuracy over traditional HE staining and has the potential to help in the expectant management of women with suspected HG CIN.?Women remain at risk of developing cervical cancer following treatment of CIN/CGIN and should be appropriately followed up.general population to 9.6% for excisional depths of 10–14 mm, 15.3% for excisions of 15–19 mm, and 18% for excision of more than 20 mm.Cervical stenosis can rarely occur after treatment. This is more common after cold knife conization or in cases of repeat excisions. Cer- vical stenosis leads to decreased cytologic and colposcopic accuracy at follow-up.It is very important to discuss these risks when counselling women for treatment especially in women who have not completed their families.TREATMENT FOLLOW-UPPatients after CIN treatment remain at risk of recurrent disease. The risk of a future cancer is approximately 4–5 times that of the background risk and usually due to poor compliance withfollow-up. Majority of recurrences are usually detected within 24 months of treatment. Other factors that contribute to the risk of treatment failure include age >40 years, high-grade le- sions, glandular lesions, and positive treatment margins. Involvement of the excision margins increases the risk of treatment failure by nearly6 times and more so, if the endocervical margin is involved. With the increased sensitivity offered by HPV testing as part of ‘Test of Cure’, repeat excisions are not advocated unless there is evi- dence of glandular/invasive disease or the wom- an is over 50 years of age.HPV test of cureAfter treatment of all grades of CIN, women are invited for screening after 6 months for LBC and HPV testing. HPV testing has higher sensitivity and negative predictive value compared with cy- tology or colposcopy alone in identifying resid- ual/recurrent disease. HPV testing in addition to LBC allows early return to routine recall if these tests are negative at 6 months.CGIN-treated patients are at higher risk of recurrent disease. If the excision was incomplete, these women should be followed up with cytolo- gy and colposcopy at 6 months, 12 months, and then annually for another 9 years. If excision was complete, then women should be offered LBC and HPV testing at 6 and 18 months and can be returned to normal recall if these are negative.Further Reading1. NHSCSP Colposcopy and Programme Management NHSCSP Publi-cation 20. March 2016.2. RCOG Scientific Impact Paper No. 21, July 2016. Reproductive Out- comes after Local Treatment for Preinvasive Cervical Disease.3. Public Health England NHS Cervical Screening Programme. . Doorbar J, Quint W, Banks L, et al. The biology and life cycle of human papillomaviruses. Vaccine 2012; 30: F55–70.? 2017 Elsevier Ltd. All rights reserved. Initially published in Obstetrics, Gynaecology and Reproductive Medicine 2017;27(6):177–183.About the AuthorsAslam Shiraz is a Specialty Registrar in the Department of Obstetrics andGynaecology at Hinchingbrooke Healthcare NHS Trust, Huntingdon, UK. Conflicts of interest: none declared.Tarang Majmudar is Consultant Gynaecologist and Lead Colposcopist at Hinchingbrooke Healthcare NHS Trust, Huntingdon, UK. He is also a BSCCP Executive Officer representing the Eastern Region. Conflicts of interest: none declared.MIMS8EMPOWERING HEALTHCARE COMMUNITIESYour ultimate guideto disease-specific informationThe MIMS Disease Resource Centre provides a wealth of information on diseases,causes,symptoms and treatment options for informed and quicker decision-making.Access online at or via the MIMS mobile app.Analgesia in Labourand DeliveryAndy Chu MBBS; Samson Ma BMedSci BMBS MRCP FRCA; Shreelata Datta BSc(Hons) MBBS MRCOG LLMPain is de?ned as “an unpleasant sensory or emotional experience associated with actual or potential tissue injury.”Labour pain is encountered during contractions in labour, and patient satisfaction correlates closely to how well it is managed. Doctors commonly encounter acute pain in clinical practice which can be treated simply by applying some basic rules. However, pain due to labour requires speci?c management which falls outside the basic principles of acute pain management and it is important for practitioners who look after these patients to understand what can be offered.This review considers the basic principles of each of these techniques using common clinical scenarios. The type of analgesia given will determine where labour takes place and this will be re?ected in each case. Speci?cally, the World Health Organization (WHO) analgesia ladder is not applicable in these patients because the periodic nature and the intensity of labour pain renders this model obsolete,although is applicable after delivery.INTRODUCTIONAnalgesia in labour is complex and canfluctuate from moment to moment de- pending on the stage of labour; eachManagement of pain during labour is very important to ensure that this is a positive experience for the woman and her partner.requiring a particular skill set and equipment. Labour analgesia can be broadly classified into regional and nonregional analgesia, with a fur- ther sub-classification of nonregional as pharma- cological and nonpharmacological. Early plan- ning and antenatal counselling are essential in a multidisciplinary clinic offering an anaesthetic opinion as well as midwifery and obstetric advice for high-risk patients with multiple comorbidities such as high BMI, difficult spinal anatomy, and previous obstetric or anaesthetist complications.Labour is a physiological process which in- volves delivery of the baby and placenta from the uterus to the outside world. Management of pain during labour is very important to ensure that this is a positive experience for the woman and her part- ner. Understanding this physiology will enhance why certain techniques are used.The type of pain experienced relates to the different stages of labour:? The first stage relates to uterine contractions.Pain signals are transmitted via Aδ and C af-ferent fibres through the sympathetic nerves to the sympathetic chain. The pain is therefore felt at T10–L1 dermatomes. Cervical pain is carried to the S2, 3 dermatomes via parasym- pathetic pelvic splanchnic nerves. Aδ fibres are thin and myelinated with a moderate speed of signal conduction. These fibres transmit acute, sharp pain. C fibres are unmyelinated and have a slower conduction velocity. C fibres primarily transmit a deep, dissipated type of pain after the initial injury.? The second stage of labour relates to the pas- sage of the baby through the birth canal, where the pain is more localized to the perineum. Pain afferents are Aδ fibres via the pudendal nerves, affecting the S2–S4 dermatomes.Case 1: Home/midwifery led unitA 30-year-old G3P3 woman in early labour, con- tracting moderately every 3–4 minutes.It is possible for labouring women to require minimal analgesia, particularly in the multiparouspatients. Nonpharmacological methods which are recognised to help in labour include the pres- ence of nonmedical trained support, such as a doula, who can provide advice before, during, or after childbirth. Other methods which have not been well-studied but may have some effect include immersion in water, relaxation, acupunc- ture, and massage. There is insufficient evidence of the effectiveness of hypnosis, biofeedback, sterile water injection, aromatherapy, and trans- cutaneous electrical nerve stimulation. Although robust scientific evidence may be lacking in the nonpharmacological methods, they remain avail- able for patient to choose and their effectiveness should be considered on an individual basis. Sim- ple analgesia such as paracetamol can be given but there is not a significant amount more than can be offered. Pharmacological solutions in this setting is rudimentary as personnel and moni- toring equipment are not available unless in a hospital setting.Case 2: Labour wardA 26-year-old primiparous patient with a histo- ry of pre-eclampsia (not requiring medication). She is 5 cm dilated, contracting 3–4 in 10 and now requesting analgesia.This particular patient is not uncommon con- sidering pre-eclampsia (PE) affects up to 8% of all pregnancies worldwide. An epidural will be benefi- cial for her, especially an early one in labour, for numerous reasons. Controlling her pain will help to control any excessive hypertensive responses. As covered in more detail later, the sympathetic blockade from the epidural can cause vasodila- tion and can improve placental blood flow to the foetus.Epidural analgesiaRegional anaesthesia, including epidurals, re- mains one of the most effective forms of pain relief in labour. This method requires the skill of an anaesthetist for insertion together with foetal and maternal monitoring after insertion. There- fore, the patient must be cared for on labourSpinal cord Dura mater Interspinous ligamentEpidural space with anaesthesiaSupraspinous ligamentLigamentum flavumSubarachnoid spaceFigure 1. Insertion of Tuohy needle into the epidural spaceward where monitoring can occur. An epidural is a “neuraxial” technique which offers reliable, effective, and flexible analgesia to patients in labour. Importantly, drugs used in this method are not spread systemically. As shown in Figure1, an epidural catheter is inserted via a Tuohy needle into the epidural space at an appropri- ate level. The anaesthetic mixture, containing a local anaesthetic (LA) and an opioid, is injected or infused into this space. The LA used is usu- ally 0.5% bupivacaine or levobupivacaine, while the opioids used are fentanyl or diamorphine. An epidural offers reliable, effective, and flexible analgesia to patients in labour. The peak onset occurs after 20 minutes, but once this has been reached, the pain relief is sustained and com- plete. An appropriate block will extend to the sacral area such that it will cover pain from the second stage of labour pain. The nerve region blocked by an epidural will depend on its prima- ry indication – for example, a block extending to T8/T10 may be sufficient to provide analgesia for labour contraction pains, whilst a denser block extending to T4 is required for a caesarean sec- tion (CS). Quite often, instrumental delivery and episiotomies may be performed without needingTable 1. Contraindications for Regional Anaesthetic BlocksAbsoluteRelativeMaternal refusalSignificant haemorrhage is expectedLocal infectionUntreated systemic sepsisUncorrected hypovolaemiaCertain cardiac diseases – shunts, where rapid BP changes are not toleratedCoagulopathy (platelets <75 x 109/litre, use of antiplatelet agents such as clopidogrel)Previous spinal injuries or surgeriesRaised intracranial pressureto “top-up” the epidural or requiring other anal- gesic techniques.The patient must be fully consented before a regional block. Contraindications are listed in Table 1 and these apply to the other regional techniques used. Due to the nature of the epi- dural, there may be lower limb motor block. This motor function deficit has been linked to prolonged second stage of labour and increase use of instrumental deliveries. Some patients may find this distressing as they are unable to mobilise. The anaesthetist will assess the effec- tiveness of the block looking at both the motor block using the Bromage scale and sensory block, then adjust the dose to patient comfort with minimal motor blockade. A different LA agent, ropivacaine instead of bupivacaine, can produce less motor blockade but is not as po- tent. Hypotension can occur due to vasodilating effects of preganglionic autonomic B fibres inhi- bition. This should be anticipated and managed as appropriate with vasopressors such as me- taraminol or phenylephrine.Epidurals can provide other benefits be- side analgesia; by blunting sympathetic nervous activities they can attenuate the sympathetic response to anxiety and pain. There is also a reduced risk of thromboembolism in the lower limbs. This regional method means that women can have skin-to-skin contact with their babiesimmediately after birth – this is a recommenda- tion by the Royal College of Obstetricians and Gynaecologists (RCOG) to improve bonding. Paradoxically, breastfeeding after having an epi- dural may be problematic. It has been found that women undergoing an epidural will have more difficulty starting an infant on breastfeeding with- in the first 24 hours. This phenomenon is not en- tirely understood but if feeding is not established within the first hour, these mothers run a high risk of needing bottle supplementation instead.Spinal tap: If the epidural catheter punc- tures an epidural vein, the LA can be injected di- rectly to the central venous system and results in toxicity even with small doses. This is particularly dangerous as epidural doses of bupivacaine are of much larger quantity than spinal doses (~20 mL vs ~2.5 mL). If the catheter pierces the dura, an excessively high block can result due to injec- tion into the subarachnoid space, which at worst can result in a total spinal block. A patient with total spinal block will require ventilatory and cir- culatory support. Epidural abscesses or haemat- omas are rare (under 1 in 160,000) and serious complications but should be considered if a pa- tient still complains of motor blockade more than6 hours after cessation of the infusion or has new onset incontinence. These conditions can result in permanent paraplegia if not identified and treated in a timely fashion. Urgent radiological imaging and discussion with the spinal team are warranted to salvage the situation before dam- age becomes permanently irreversible.Epidural block: An epidural block has a similar side-effect profile to that of a spinal. There is a risk of infection in procedures and a spinal infection can be particularly catastrophic, requir- ing potent and lengthy antibiotic treatment. Loss of sterility can be a risk during a difficult injec- tion requiring multiple attempts. Direct injury to the spinal cord is rare, but the majority of these patients will make a full recovery from nonper- manent nerve injuries. One point of note is that patients under regional anaesthesia are espe- cially sensitive to sedation and therefore at riskof respiratory depression. A large dose of opioid given intrathecally can cause severe pruritus, which can be more distressing than the pain itself. This can be alleviated with antihistamine medications.Alternative regional block techniques available to women without an epidural in second stage of labourWhere regional block techniques using spinal block cannot be performed, other regional tech- niques such as the pudendal and paracervical blocks, performed by the obstetricians, can be applied in the labour ward to help with the reliefof labour pain. The nerve pathways blocked areSegmental epiduralLumbar sympatheticLow caudal/true saddle blockParacervical block S2–S3Pudendal block S2–S4Paravertebral blocks T10–L1Sacral nerve-root blocks S2–S4demonstrated in Figure 2.Pudendal nerve block: During the second stage of labour, pain is experienced in the low- er vagina, vulva, and perineum. The pudendal block is a technique that can cover these areas (S2–S4) via direct injection of local anaesthetic to the pudendal nerve area using a trumpet nee- dle via transvaginal route. However, this stage is usually very short and this block is usually used to cover pain from instrumentation and episioto- mies or perineal tear repair during delivery. Note that the anterior perineum (ilioinguinal nerve) is not blocked so a local infiltration is often used around the perineum as well to anaesthetise the skin. In these situations, it is important to calcu- late a predetermined maximum local anaesthetic dose and make sure this is not exceeded to pre- vent complications of toxicity. Failure or inade- quate block is common, with a failure rate of 50% even in experienced hands.Paracervical block: The paracervical block is rarely used for analgesia during the first stage of labour. It aims to block the paracervi- cal ganglion, which lies lateral and posterior to the cervicouterine junction. Whilst this provides analgesia without the sensory or motor block- ade seen in epidurals, it does not relieve uterine contractions and can result in foetal bradycardia, typically occurring 2–10 minutes from injection. It can be difficult to administer and is thereforeFigure 2. Nerve pathways transmitting labour pain and the available nerve blocks that can be used to block themnot commonly performed. Both the pudendal and paracervical blocks rely on blind techniques performed transvaginally. Thus, there is always a risk of needlestick injuries to the physician.Case 3: Labour wardA 30-year-old primiparous woman who is 8 cm dilated contracting 3:10. Platelet count was 40 x109/litre with contraindications to a regional an- algesic approach.Mx issues: Besides controlling this patient’s pain, there are pressing issues that trouble the anaesthetic and obstetrics team for this woman in regards to her labour. With a thrombocytopenia, HELLP/PET must be considered with increased attention paid to her blood pressure and neuro- logical status. With a platelet level this low, a re- gional anaesthetic approach should be avoided. A thrombocytopenia of this severity poses prob- lems for delivery of the baby as a platelet level of at least 50 x 109/litre is required. Input from a hae- matologist would be beneficial for advice and ac- quisition of blood products. A general anaesthetic may well be required for this parturient woman with such a coagulopathy if a surgical delivery occurs.Analgesic control in labour can be es-The use of Entonox in labour is well established as demonstrated by its availability throughout nearly all the obstetrics units across the United Kingdom.tablished by using systemic pharmacological agents, although potentially this method is infe- rior to appropriately placed regional techniques. As listed before, an epidural may not be possible in some patients. The below listed methods are the commonly used ones in labour ward settings and can be achieved relatively easily without specialist input. It is important to discuss the methods with each patient appropriately as ac- ceptable analgesia does not necessarily mean absolute absence of pain.Entonox: Entonox is the trade name of 50% oxygen and 50% nitrous oxide gas mixture. It is an anaesthetic gas frequently used in hospital A&E, labour wards, and midwifery led units. The use of Entonox in labour is well established as demonstrated by its availability throughout near- ly all the obstetrics units across the United King- dom. One reason for its popularity is its ease of use in the first stage of labour, although the pa- tient must be counselled on how to use it effec- tively – it is delivered using a mouth nozzle heldby the patient. The gas is inhaled and reaches a peak effect by 20–30 seconds – ideal for inter- mittent intense pain seen in labour. The neonate eliminates most of the gas within minutes of birth so there is low risk of respiratory depression. Nausea, vomiting, and disorientation are com- mon side effects, but the major disadvantage of Entonox is its inability to provide complete anal- gesia. Nitrous oxide is highly lipid-soluble and will expand luminal spaces it diffuses into. Cer- tain circumstances such as bowel obstruction, pneumothorax, ongoing middle ear infections, and decreased levels of consciousness will limit its use.Pethidine: Pethidine, also called meperidine, is an opioid about one-tenth as potent as mor- phine and can be given intramuscularly. Pethidine is widely used in labour and can be prescribed and administered by midwives. Side effects of pethi- dine are similar to those of other opioids, namely respiratory depression of the mother and neonate, delayed gastric emptying, nausea, vomiting, se-dation, and hypotension. As pethidine is highly lipid-soluble, it crosses the placenta and foetal ex- posure to this drug is maximal at 2–3 hours after maternal intramuscular administration. The optimal time for delivery of the baby following a dose of pethidine is either within the first hour or after the fourth hour of dosing. If pethidine is used within4 hours of delivery of the baby, the paediatrician should be informed and asked to attend the de- livery in case any neonatal respiratory support is needed. Hence, whilst pethidine can be given eas- ily, good attention to timing and access to assis- tance are still required.Morphine & diamorphine: Morphine can be administered intravenously or intramuscular- ly and reaches maximal effect at 20 minutes and1–2 hours, respectively. Despite being significantly less efficacious than regional techniques with side effects common to all opioids affecting the moth- er and baby, systemic opioids are still used for a number of reasons. These include ease of ad- ministration, low cost, and patient’s perception of reduced risk compared to epidurals.Diamorphine is not commonly used in ob- stetric units across the nation. It is more lipid-sol- uble than morphine and therefore more potent and has a faster onset of action. While diamor- phine provides good analgesia, it is found that the length of labour is significantly increased with its use so therefore more pain is experienced overall.Patient-controlled analgesiaPatient-controlled analgesia (PCA) refers to self-administration of intravenous opioid drugs by a preset intravenous infusion pump. This is set up by anaesthetists on labour ward and allows each patient to receive an appropriate dosage of analgesics suitable to their respective needs at a particular time. Fentanyl and remifen- tanil are commonly used. Both are potent syn- thetic opioids with rapid onset and short duration of action. Fentanyl has a potency of roughly 100 times that of morphine but crosses the placenta quickly and can accumulate in the foetus if large doses are used.PCA is only considered in modern obstetric units when epidural had been declined or contraindicated.Remifentanil is a relatively new ?-recep- tor agonist. It is even more potent than fenta- nyl and is described as “ultra short-acting,” with an onset period of 1 minute and constant context-sensitive half-life of 3.5 minutes. This property of remifentanil makes it an ideal can- didate for PCA in labour analgesia since even prolonged use will not cause accumulation in the tissue.However, PCA is not considered first-line for labour analgesia as medication is administered systemically – side effects can affect mother and foetus. PCA requires close supervision to avoid maternal hypoventilation, so the patient must be on labour ward and the lack of adequately trained staffs to care for patients with it is a con- traindication for use. Therefore, PCA is only con- sidered in modern obstetric units when epidur- al had been declined or contraindicated – or in situations where systemic use resulting in foetal harm is not an issue such as in intrauterine foetal death with normal delivery.A patient with total spinal block will require ventilatory and circulatory support.Case 4: Operating theatreA 30-year-old primiparous woman requiring an elective caesarean section (CS) for breech presentationData from RCOG suggest between 25 and 30% of deliveries in the UK are by CS. The choice of analgesia, or anaesthetic, techniques depends on urgency of the case, indication for CS and patient choice. This should be discussed with the obstetrician to ensure the most appro- priate technique is performed. In these scenari- os, the patients would require sufficient pain re- lief, which most often comes from an anaesthetic intervention, to allow for the surgery.Spinal anaestheticIn elective CS, the regional technique is pre- ferred over general anaesthetic (GA); this avoids the increased risks associated with GA in preg- nancy such as difficulty in intubation, aspiration risk, and possible ventilatory difficulties. In addi- tion, the patient is awake and her partner is al- lowed to accompany her in the theatre, allowing early bonding with the baby, and higher chances of initiating breastfeeding.The regional technique of choice is usually a single-shot spinal anaesthesia. Spinal anaes- thesia offers simple, rapid, and dense blockade with negligible maternal and infant risk of local anaesthetic toxicity and respiratory depression. The level of injection must be below L2/L3 to avoid damage to the spinal cord. Bupivacaine0.5% mixed in 80 mg/mL of glucose is most com- monly used by obstetric anaesthetists in the UK. The glucose renders the solution “hyperbaric” and denser than CSF. It sinks with gravity when injected into the spinal space – this allows con- trol of LA spread. After injection, the patient must be in a supine position and possibly with head down tilt to encourage spread up to an appro- priate level. An injection of 2.5 mL of 0.5% heavy bupivacaine plus a precalculated dose of fenta- nyl or diamorphine can usually cover the surgical duration and provide postoperative analgesia. A spinal anaesthetic can also be administered to women undergoing instrumental delivery in the- atre, who do not have an ongoing epidural or one that is not working optimally.As mentioned previously, a large spinal dosage can result in a high or total spinal block,which if not recognized can lead to life-threaten- ing hypotension from vasodilatation or respirato- ry failure due to blockade of the diaphragm and intercostal muscles. The toxic dosage of bupi- vacaine is 2 mg/kg (with or without adrenaline) with a maximum dose of 150 mg. First signs of toxicity are usually cerebral in nature – dizziness, confusion, metallic taste, lip tingling, or seizures. At severe toxicity, bupivacaine is cardiotoxic and can cause complete cardiovascular collapse from a combination of peripheral vasodilatation and myocardial contractility depression. Patients should already have large bored venous access prior to any regional blocks. The usual resusci- tative equipment and procedures are needed. If cardiac arrest has occurred, ALS protocol should be started along with securing of the air- way. An intralipid emulsion can be used as ‘an- tidote’. This emulsion serves to chelate the local anaesthetic agent and can be started as a bolus of 1.5 mL/kg. The patient would need monitoring or continuing care in HDU/ITU following this.Epidural for surgical deliveryBy and large, epidurals are removed immediately postoperatively unless there is a high risk of the need to return to theatre. However, if an epidural is present in women undergoing an instrumental delivery, a larger dose of opioid can be injected into the epidural space to “top-up” analgesia.For surgery, an indwelling catheter can be topped up, as shown in Figure 3, to extend the level of nerve block to T4 level. This would al- low sufficient coverage for a CS. The epidural catheter is usually removed 1–2 hours postop- eratively and can be done so by a nurse or an bined spinal epiduralThe combined spinal epidural (CSE) is an amal- gamation of a spinal injection with placement of an epidural catheter in one procedure. This method exploits the rapid and dense neuraxial block of the spinal anaesthesia as well as the ability to prolong the block via the epidural route.Extension to T4 level for emergency CSGeneral area of numbness from T8–T10 level epidural for contraction painEPIDURAL DURING LABOURCaudal extension to T4 level is required for emergency CS by top-upFigure 3. Area of nerve block provided by an epidural analgesia for contraction pain (T8 – T10)This technique allows prolonged analgesia when operation time is expected to surpass the dura- tion of a single spinal injection. An example is a woman with twin pregnancy who is at risk of uterine atony post-delivery and may take longer operating time for haemostasis to be achieved– in this case, the epidural inserted in the space can be topped up for surgical analgesia.The CSE can be applied not only for oper- ative analgesia but can also be put in place of the epidural for a woman in active labour. The initial spinal block, lasting 1–2 hours, provides quick, and intense pain relief that surpasses that of an epidural. Intermittent low doses of bupiv- acaine can be applied through the epidural af- ter the spinal injection wears off. A lower dose of bupivacaine is used, meaning most patients undergoing the CSE during labour will maintain the ability to ambulate – something which the conventional epidural often inhibits. The RCOG states that there is no difference between rates of operative vaginal (instrumental vaginal deliv- ery) using CSE compared with an epidural. The epidural remains the gold standard in obstetrics analgesia, so it will depend on future studies to see if the CSE will increase in popularity.Practice Points?The normal WHO method of analgesia does not offer the best analgesia during this period.?Patient’s perception and acceptance of what is controlled pain relief is just as important as providing the appropriate analgesia.?Patient’s level of analgesia needed will determine where their delivery takes place.?Regional techniques are more effective than systemic methods of analgesia.?Regional techniques are the preferred methods for surgical deliveries.The complications are very similar to those in spinal and epidurals except for a few rare ones. Migration of the epidural catheter is a the- oretical risk as there is a punctured hole in the dura from the spinal injection itself, so any further top-ups should be handled carefully. Therefore, high blocks must always be taken into account, especially if large epidural boluses are given.Case 5: Operating theatreA 29-year-old primiparous patient requiring an emergency category 1 CS for foetal distress at3 cmCS are classified from category 1–4 based on the urgency:? Category 4: Elective CS? Category 3: Expedited delivery with no mater- nal or foetal compromise? Category 2: Maternal or foetal compromise but not immediately life-threatening? Category 1: Maternal or foetal compromise that is immediately life-threateningGeneral anaestheticCategory 2–4 CS are generally done under regional techniques (ie, spinal). A category 1 CS (immediate delivery) may require a GA if a regional technique might not provide adequate anaesthesia in time. However, a regional technique is favoured over GA even in a category 1 section. The aim in these cases is to deliver the foetus as quickly as possi-ble while minimising risks to the mother. However, the anaesthetist must be in communication with the obstetric team regarding the state of the foetus and be ready to convert into GA should it be required.GA CS is not commonly done. The major risks of this technique will be linked to the airway. Due to anatomical and physiological changes in pregnancy, failed intubations are 10 times more common and this can be further plagued by the lack of anaesthetic experience due to limited training opportunities. Risks of acid regurgita- tion and aspiration are twice as likely compared to the nonpregnant patient due to progester- one reducing the lower oesophageal sphincter tone. Antacid prophylaxis such as H2 antago-nists and prokinetics should be considered priorto induction of GA. A rapid sequence induction technique with adequate preoxygenation should be performed to minimise the time between ad- ministration of induction agents to securing the trachea with an endotracheal tube. Of the four maternal deaths directly related to anaesthesia in the latest maternal mortality, MBRRACE-UK report, two were linked to patients under general anaesthesia and subsequent airway problems. Failed intubation should be anticipated and res- cue methods and equipment readily at hand in all obstetric general anaesthetics.Post GA CS pain relief: Appropriate anal- gesia remains vital as anaesthetic agents do not supply sufficient pain relief. In a GA CS, local anaesthetic injection for transversus abdominal plane block applied intraoperatively may help re- duce the requirement of systemic opioids postop- eratively. Another method is the infiltration of local anaesthetic to skin incision after closure. Howev- er, these patients may still need a PCA postopera- tively. Minimal amounts of opioids are transferred via breast milk. Regardless, the mother and new- born should be monitored appropriately and the PCA stopped should any drowsiness is observed.ANALGESIA AFTER DELIVERYAnalgesia should be prescribed as per the WHOanalgesic ladder. This algorithm was initially cre-ated to treat cancer pain, but its stepwise ap- proach has been applied to clinical situations in- cluding acute pain (see Figure 4). The principle is to initially treat with the simplest drug and add on more potent analgesia in a stepwise fashion. This ensures a multimodal approach, which in- creases efficacy, and reduces the accumulative side-effect profiles of the drugs. Patients often request the strongest analgesics and may ques- tion physicians when given weaker medications.It is important to explain the WHO model to pa-Step 1Nonopioid (eg, aspirin, paracetamol, or NSAID)± adjuvantStep 2Week opioid for mild to moderate pain (eg, codeine)± nonopioid± adjuvantPain persisting or increasingStep 3Strong opioid for moderate to severe pain (eg, morphine)± nonopioid± adjuvantPain persisting or increasingPain controlledtients as this allows the patient to understand the rationale behind their treatment.Strong opioids like morphine should be prescribed in conjunction with their predeces- sors, and not alone at the very beginning in or- der to exploit the synergistic effects of combined analgesia.Patients may question about the safety of these drugs in terms of breastfeeding. Morphine delivered via PCA method can be transferred through breastFigure 4. Stepwise approach recommended by the WHO analgesia ladderEpiduralPCA using fentanyl/ remifentanilIM/IV morphine or diamorphinemilk but it does not seem to cause adverse foetalrespiratory depression, possibly from significant fist-pass metabolism. NSAIDs, apart from aspirin, are considered safe to use as well.CONCLUSIONWhilst there is no official pain ladder when deal-Natural methods (positioning, breathing exercises, hydrotherapy,mobilizing, and TENs) Simple analgesics:EntonoxIf epiduralcontraindicated, declined, or impossiblePethidineing with women who are in labour, Figure 5 out-lines a generic approach which can be applied to patients in labour. Patients will have differentparacetamolIncreasing/persisting painrequirements and may have prearranged expec- tations and successful labour analgesia can be challenging for individual patients, with different approaches needed at different stages. All preg- nant women should discuss analgesia in labour during their antenatal appointments, document- ing their preferred methods in their birth plan. This may need to be revised or reaffirmed once the patient is in established labour.Further Reading1. Allman K, Wilson I. Oxford handbook of anaesthesia. 4th Edn. New York:Oxford University Press, 2016.2. Aitkenhead A, Moppett I, Thompson J. Smith & Aitkenhead’s textbook of anaesthesia. 6th edn. Elsevier Limited, 2013.3. Chestnut DH. Obstetric anaesthesia: principles and practice. 3rd edn.2004. Philadelphia: Elsevier Mosby, 2004.Figure 5. Managing pain in labour – the 'Obstetric Iabour' pain ladder4. Rucklidge M. Analgesia for labour. Anaesthesia UK ATOTW Archive. (accessed 16 Jul2014).5. The Royal College of Obstetricians & Gynaecologists. Green-top Guide- line No. 26: Operative vaginal delivery. sets/documents/guidelines/gtg26.pdf.? 2017 Elsevier Ltd. All rights reserved. Initially published in Obstetrics, Gy- naecology and Reproductive Medicine 2017;27(6):184–190.About the AuthorsAndy Chu is a CT1 in Anaesthesia at Kingston Hospital NHS Trust, Kingstonupon Thames, UK. Conflicts of interest: none declared.Samson Ma is an ST6 in Anaesthesia at St George’s Hospital NHS Trust, London, UK. Conflicts of interest: none declared.Shreelata Datta is a Consultant Obstetrician and Gynaecologist at King’s Col- lege Hospital NHS Trust, London, UK. Conflicts of interest: none declared.Acute Kidney Injuryin Paediatric Critical CareRupesh Raina MD; Abigail Chauvin; Akash Deep FRCPCH MDIncidence of acute kidney injury (AKI) is gradually increasing in children admitted to critical care units partly because of increased awareness of this entity. Though serum creatinine has been used in most de?nitions, its inability to accurately re?ect kidney function has resulted in problems for clinical research in paediatric AKI. This has resulted in the use of more than 35 de?nitions of AKI in clinical studies, ranging from small changes in serum creatinine to requirement for dialysis. Therefore, comparisons among studies are dif?cult, resulting in a wide range of quoted epidemiology, morbidity, and mortality rates in the AKI paediatric literature. Acute kidney injury may be precipitated by critical illness, pre-existing medical conditions, and treatments received both before and during ICU admission. In this review, we have attempted to outline the current de?nitions used for AKI, presence of AKI in various critical care conditions (bone marrow transplant, liver, sepsis, cardiac, and primary renalconditions leading to glomerulonephritis), and outline the basic management.INTRODUCTIONAKI is a complex condition with numer- ous pathologies, in which there is spo-radic failure and rapid loss of renal func- tion. It is fairly new terminology for what was previously referred to as “acutekidney failure.” AKI is detected by a marked de- crease in glomerular filtration rate (GFR), accom- panied by elevated levels of serum creatinine. This disease is associated with a poor prognosis resulting in longer hospital and intensive care stays and higher mortality rates. It is difficult to present an accurate incidence of AKI since dis- ease presentation and definitions are variable, however it is estimated to vary between 8% and30% in paediatric intensive care units. Prognosis for these patients depends on the underlying ae- tiology, ranging from full recovery to end-stage renal failure (ESRF).EPIDEMIOLOGYThe interpretation of AKI depends on which cri- terion is being used, as well as the geographic location it is being diagnosed in. The incidence of AKI in critical care environments diagnosed using the Kidney Disease: Improving Global Out- comes (KDIGO) criteria is approximately 40%.The mortality rate in hospitalized patients with AKI was found to be 14.7% greater than in hospitalized patients without AKI. Increased incidence of AKI was found to be associated with male, Afro-American ethnicity, and being aged 15–18 years. Additionally, neonates have a significantly higher mortality rate and median length of stay in the hospital.AETIOLOGY AND PATHOPHYSIOLOGY The aetiology of AKI may be prerenal, renal, or postrenal. Prerenal AKI is due to renal ischaemia as a consequence of systemic hypovolaemia. This occurs for a variety of reasons: diarrhoea, haemorrhage, dehydration, decreased cardiac output/contractility, and sepsis. Prerenal AKI is the most common type of AKI in children, and activates homeostatic compensatory mecha- nisms to restore renal perfusion.Intrinsic-renal AKI occurs when internal re- nal structures are damaged. Conditions causing intrinsic AKI include: ischaemia, nephrotoxic drugs, glomerular disease, and microvascular disease (see below). Tubular cells of the straightsegment of the proximal tubule and the thick as- cending limb of the loop of Henle are especially susceptible to ischaemic insult, due to high ATP demands and naturally hypoxic environment, respectively. Hypoxic and nephrotoxic drug-in- duced injury has been found to lead to elevated risk of CKD long-term.Postrenal AKI occurs due to obstruction after the level of the kidneys. Typically, AKI is alleviat- ed upon removal of the obstruction. Additionally, if the individual has two functioning kidneys, the blockage must be bilateral in order to result in AKI, otherwise the functional kidney will compensate.Diseases of intrinsic-renal AKIAcute tubular necrosis (ATN) results from renal ischaemia-reperfusion injury. Due to hypoxia, accumulation of metabolites, and insufficient nu- trition, tubular epithelial cells are damaged and may progress to apoptosis or necrosis. Homeo- stasis of water, metabolic waste, and electrolytes is imbalanced. Small arterioles in the outer me- dulla constrict and are obstructed by leukocyte accumulation and complement activation in re- sponse to inflammation, weakening the endothe- lium. Increased vascular permeability causes fluid leak into the interstitium and oedema en- sues, causing further ischaemia. Additionally, the proximal tubule is ineffective in ion transport. Therefore, the macula densa initiates further va- soconstriction of the afferent arteriole.Acute cortical necrosis (ACN) constitutes2% of all cases of renal failure in adults and ap- proximately 10% of all cases of ACN are children. Common aetiologies of ACN in children include placental abruptions, fetomaternal or twin-twin transfusion, dehydration, trauma, sepsis, renal vein thrombosis, haemolytic anaemia (severe), haemolytic uraemic syndrome, nephrotoxic drugs, and contrast substances.Haemolytic uraemic syndrome (HUS) is a form of thrombotic microangiopathy and occurs in two forms: typical and atypical. A Shiga tox- in released from Escherichia coli causes typical HUS, and atypical HUS (aHUS) can occur dueTable 1. RIFLE Guidelines from Bellomo, et al, 2004RIFLEGlomerular filtration rate (GFR)Urine output (UO)Sensitivity vs specificityCategories of kidney dysfunctionRiskSCr 1.5 times baseline or ? GFR >25%<0.5 mL/kg/hour for 6 hoursHighly sensitiveInjurySCr 2 times baseline or ? GFR >50%<0.5 mL/kg/hour for 12 hoursFailureSCr 3 times baseline or ≥4 mg/dL;? GFR 75%<0.3 mL/kg/hour (oliguria) for 24 hours(or anuria for 12 hours)Highly specificClinical outcomesLoss of functionPersistent AKI RRT >4 weeksESRDEnd-stage renal diseaseDialysis >3 monthsto a variety of conditions including congenital or acquired complement system defects and genet- ic mutations. Atypical HUS is differentiated from thrombotic thrombocytopenic purpura (TTP) by levels of ADAMTS activity, with aHUS indicated by more than 5% ADAMTS activity. If it is less than5%, the patient will be classified with TTP.DIAGNOSTIC CRITERIAAKI is a fairly new term that has replaced the no- menclature of “acute kidney failure.” Diagnosis of AKI is carried out using the RIFLE or pRIFLE, AKIN, or KDIGO guidelines. These criteria have attempted to consolidate the varying definitions of AKI in order to more consistently treat and evaluate patients.RIFLEIn May 2002, the Acute Dialysis Quality Initiative group (ADQI) met in Vicenza, Italy to establish a more concrete definition of AKI, as well as di- agnostic guidelines. The criteria established are known as “RIFLE”, an acronym for: ‘Risk of re- nal dysfunction’, ‘Injury to the kidney’, ‘Failure of kidney function’, ‘Loss of kidney function’, and‘End-stage kidney disease’. The risk, injury, and failure categories indicate stages of kidney dys- function, while the loss and end-stage catego- ries serve as outcomes.Serum creatinine (SCr) is used to estimate the GFR, and is calculated as the change be- tween current measurement and baseline. One weakness of this model is that the baseline SCr is frequently unknown, in which case the ‘modifi- cation of diet in renal disease’ (MDRD) formula is utilized to estimate baseline GFR. Table 1 sum- marizes these guidelines.AKINThree years later, in 2007, the AKI Network (AKIN) published an updated version of RIFLE, and this classification is known as “AKIN” criteria. The three subcategories of AKIN are: ‘Risk’, ‘Injury’, and ‘Failure’. Data have shown that SCr changes in smaller increments than accounted for in RIFLE guidelines may correlate to adverse outcomes. Therefore, it is thought to be more beneficial for AKI diagnostic criteria to be more sensitive to recognize and treat as early as possible to avoid ESRD. Table 2 shows the AKIN criteria.KDIGOThe most recent model for AKI diagnosis is by the KDIGO Work Group. Established in 2012, this classification is designed to further expand upon the AKIN definition. KDIGO defines AKI with the following criteria: at least 1.5-fold elevat- ed SCr within the past 7 days, elevated SCr by≥0.3 mg/dL within 48 hours, or UO equal to or less than 0.5 mL/kg/hour over 6 hours. See Table3 for guidelines.pRIFLEIn children specifically, a paediatric adaptation of RI- FLE was created, known as pRIFLE. pRIFLE differs from typical RIFLE classifications in that the classifi- cation is based on changes in estimated creatinine clearance or UO, instead of change in SCr which is used in adult RIFLE. There are three classifications:‘Risk’, ‘Injury’, and ‘Failure’. This is because children are rapidly growing, which can lead to changes in SCr independent of actual onset of AKI.AKI IN SEPSISStudies report 45–70% of AKI to be induced by sepsis. AKI and sepsis independently increase mortality, but combined sepsis and AKI shows a staggering mortality of 57–66%. Septic AKI oc- curs due to a combination of alterations in mi- crovascular blood flow, ion balance, oxidative stress, and inflammation. Traditionally, the ide- ology that renal ischaemia is the major cause of AKI lead to the thought that restored perfusion via increased RBF would resolve AKI, however studies have shown that is not the case. RBF is not thought to significantly influence septic AKI in paediatric patients.Sepsis is marked by systemic arterial vas- odilation, largely mediated by nitric oxide (NO). Inflammatory cytokines elevate production of in- ducible NO synthase, resulting in an increased NO release, and drop in arterial resistance. Also, vascular endothelial cells are resistant to pres- sor hormones. ATP-sensitive potassium chan- nels are activated during sepsis due to elevated plasma [H+] and [lactate], as well as depressed [ATP] in smooth-muscle cells of the vasculature. Hyperpolarization due to potassium efflux oc- curs, causing voltage-gated calcium channels to close, leading to further resistance to vaso- pressors. Pressor hormone receptors are also down regulated due to overproduction of the hormones, further impairing the vasculature.Table 2. AKIN Guidelines from Mehta, et al, 2007StageSerum creatinineUrine output1?SCr ≥0.3 mg/dL or 1.5–2.0times baseline value<0.5 mL/kg/hour for >6 hours2?SCr >2.0–3.0 times baseline<0.5 mL/kg/hour for >12 hoursa3?SCr ≥4.0 mg/dL with acuteincrease of ≥0.5 mg/dL or? SCr >3.0 times baseline<0.3 mL/kg/hour for 24 hours or anuria for 12 hoursaAny patients being treated with RRT automatically are placed into stage 3.Table 3. KDIGO Guidelines from KDIGO AKI Work Group 2012StageSerum creatinine (SCr)Urine output1?SCr ≥0.3 mg/dL or 1.5–1.9times baseline value<0.5 mL/kg/hour, 6–12 hours2?SCr 2.0–2.9 times baseline<0.5 mL/kg/hour, ≥12 hours3a?SCr ≥4.0 mg/dL or 3.0 timesbaseline or in patients under18 years, ? eGFR to <35 mL/minute/1.73 m2<0.3 mL/kg/hour, ≥24 hours or anuria for ≥12 hoursaAny patients being treated with RRT automatically are placed into stage 3.Since angiotensin II and norepinephrine do not restore normal vascular resistance, alter- native treatments must be considered. Current- ly, the most promising agent for vasopressor-re- sistant sepsis is arginine vasopressin, which is thought to deactivate the ATP-mediated potas- sium channels, decrease expression of NO syn- thase, and reduce cGMP signalling with NO. Ar- ginine vasopressin has a vasoconstrictive effect by targeting the efferent glomerular arteriole to increase intraglomerular pressure. However, caution must be used since arginine vasopres- sin lacks cardiac ionotropic qualities and can lead to depressed cardiac output (CO). Lastly, nonspecific effects of arginine vasopressin can cause myocardial infarction and reduced com- pliance of splanchnic vessels, leading to non- cardiogenic pulmonary oedema.AKI is detected by a marked decrease in GFR, accompanied by elevated levels of serum creatinine.Endothelin is a potent vasoconstrictor that has also been shown to play an active role in the complex pathophysiology of sepsis. TNF-α causes endothelin release, which acts on vascu- lar endothelial cells and causes microvascular fluid leakage. Inflammation also plays a central role in septic AKI. Inflammatory cytokines lead to heterogeneous upregulation of inducible NO synthase, damaging various regions of the mi- crovasculature.RAPIDLY PROGRESSIVE GLOMERULONEPHRITISRapidly progressive glomerulonephritis (RPGN) is indicated by decreased renal function and is often associated with haematuria, proteinuria, and decreased UO. This condition is frequent- ly referred to as crescentic glomerulonephritis (CGN), since it is marked by development of glomerular crescents. Glomerular crescents are nonspecific response to glomerular injury, ap- pearing as ≥2 layers of cells in the Bowman’sspace of the glomerulus, constricting the glo- merular capillary tuft. Crescent formation is initi- ated by holes in the glomerular basement mem- brane (GBM), Bowman’s capsule, and walls of glomerular capillaries allowing macrophages and coagulation factors to trigger cleavage of fibrinogen to fibrin. Earlier commencement of medical intervention will help to avoid long-term damage.NEPHROTOXIC AKINephrotoxic medications are substantial cause of AKI, reported as 16% of AKI in hospitalized paediatric patients. Certain antibiotics, antivirals, antifungals, angiotensin converting enzyme in- hibitors (ACEIs), nonsteroidal anti-inflammatory drugs (NSAIDs), calcineurin inhibitors, chemo- therapeutic agents, and radiographic contrast substances induce nephrotoxic AKI.Cisplatin is a platinum-based chemother- apeutic agent typically utilized in the manage- ment and treatment of solid, malignant neo-plasms. One in every three patients treated with cisplatin experiences nephrotoxicity. Proximal tubule injury, consequent oxidative stress and inflammation, and direct toxicity to renal vascu- lar endothelial cells cause AKI. Currently, sup- portive therapy is the typical intervention. Con- trast substances are the third most common aetiology of AKI in hospitals. Presentation is typically nonoliguric, with transient loss in renal function. The pathological mechanism consists of increased renal blood flow (RBF) initially, fol- lowed by decreased RBF and eGFR. The fall in eGFR is also contributed to by constriction of the vasa recta, medullary ischaemia, reactive oxygen species (ROS) generation, and injury to tubular epithelial cells.Recently, a retrospective cohort study of100 children with AKI due to exposure to high levels of nephrotoxic medications in a noncritical setting was performed at Cincinnati Children’s Hospital Medical Center. Researchers found that patients with nephrotoxin-induced AKI were3.84 times more likely to develop 1+ signs of CKD. Additionally, the AKI cohort was found to have significantly decreased eGFR and higher likelihood for hypertension and proteinuria at 6 months.To manage paediatric nephrotoxic AKI, cease treatment with the toxic agent as soon as possible and prevent exposure to future nephro- toxins to preserve renal function. Fluid therapy should target restitution of renal perfusion. In severe cases, renal replacement therapy (RRT) may be utilized for the purpose of toxic solute removal.AKI IN BONE MARROW TRANSPLANTATIONAKI is a common complication of haematopoie- tic stem cell transplantation (HSCT), otherwise commonly known as bone marrow transplants. Patients with HSCT-induced AKI requiring RRT have a disappointingly low survival rate of 42%. It is reported that the incidence of paediatric HSCT-induced AKI is between 25% and 30%.AKI and sepsis independently increase mortality, but combined sepsis and AKIshows a staggering mortality of 57–66%.Pheresis may contribute to graft versus host disease (GVHD) due to differing immunologi- cal composition to marrow. GVHD accompa- nied by renal disturbance is reported to occur in 11–41% of paediatric patients who receive HLA-matched BMT. However, peripheral HSCT collection leads to reduced rates of sepsis, cy- topaenia, and need for nephrotoxic antibiotic therapy after transplantation.Sinusiodal obstruction syndrome (SOS), also referred to as veno-occlusive disease (VOD), commonly occurs with BMT. The exact pathophysiology is not yet known, but current literature points to injury to hepatic sinuos- oids. Despite lack of empirical evidence about SOS-induced paediatric AKI in BMT, it is well known that SOS/VOD is a significant risk factor for AKI development. AKI in SOS is thought to pathologically behave similarly to hepatorenalsyndrome (HRS) with regards to haemodynam- ic shifts, as well as liver impairment resulting in hypoalbuminaemia, fluid leakage from capillar- ies, splanchnic vasodilation, and hypovolaemia in the intravascular compartment. Chemothera- peutic drugs commonly utilized in BMT are also a source of AKI due to nephrotoxicity. Norepi- nephrine from the activated hepatorenal sym- pathetic nervous system constricts the afferent renal arteriole, depressing GFR, and retaining salt. The prognosis of SOS-AKI is poor, and thus treatment usually is supportive: treatment for the kidneys mirrors treatment of HRS, and defibrotide tends to be the drug of choice.AKI IN LIVER DISEASEAKI in liver disease can occur in patients with acute liver failure (ALF), chronic liver disease, acute on chronic liver failure, and post-transplan- tation. The most important point to bear in mind is that AKI in these patients is not always hepa- torenal syndrome (HRS). In fact, of all the caus- es of AKI in patients with liver disease, majority are caused by prerenal or acute tubular necro- sis and HRS constitutes only a small part. ALF is a rare condition, indicated by new onset liver dysfunction with coagulopathy which in children may or may not be accompanied by encepha- lopathy, AKI, and ALF often occur concurrently, especially with specific aetiologies: nephrotoxic medications, acetaminophen overdose, HRS, sepsis, and hypovolaemia.As liver disease progresses, there are se- vere vascular haemodynamic complications that disturb renal processes, leading to imbal- anced electrolyte levels and ascites. Frequent- ly, changes in vascular compliance and renal perfusion culminate in AKI, common in patients with chronic liver disease (CLD). CLD causes haemodynamic fluctuations, unbalancing fluids and electrolytes, and leaving the kidneys highly susceptible to damage. Ascites is an indicator of this disease state in both children and adults, and serves as a mortality predictor. However, the pathophysiology of ascites in children is notcompletely understood at this point in time, so children must be treated based on adult models of disease.AKI in cirrhotic patients tends to be either prerenal or intrarenal. Depending on the aetiolo- gy, fluid management will differ: in prerenal AKI, fluid supplementation is necessary to elevate the intravascular volume while in intrarenal AKI decreasing fluids may be necessary. If ascites is severe, abdominal compartment syndrome could be the cause. Many traditional biomarkers will overestimate renal function due to problems rooted in declining hepatic function, and more accurate markers such as inulin are unrealistic in practice due to high cost and feasibility of use. However, the Modification of Diet in Renal Disease (MDRD) Study equation can be used in patients with liver cirrhosis.HRS causes prerenal AKI in patients with ascites and cirrhosis of the liver. The whole pro- cess is precipitated by portal hypertension which causes bacterial translocation and release of vas- odilators especially nitric oxide. The kidneys will attempt to salvage as much perfusion as possible by arteriole vasodilation via prostaglandins. How- ever, with low cardiac output state, activation of renin-angiotensin-aldosterone system leads to re- nal vasoconstriction and eventual ascites due to sodium and water retention.AKI IN CARDIAC DISEASEAKI commonly occurs in patients undergoing car- diac surgeries, with increased mortality and mor- bidity, as well as increasing costs of healthcare overall. Incidence of AKI after cardiac surgery ranges from 3% to 30%. A large retrospective cohort study seeking to determine the incidence of AKI in the cardiac postoperative paediatric population found that patients with AKI were more likely to have had a more complex surgery requiring lengthier cardiopulmonary bypass, cyanosis, and requirement of mechanical venti- lation. Of this subset of patients, 1–5% required RRT for AKI, and those patients additionally have a heightened mortality rate of 60%.In one study by MacDonald, et al, it was found that AKI occurred in 73% of subjects, with95% occurring within the first 3 days post-trans- plant. Significant risk factors for AKI within this paediatric group included ventilation at the time of transplant (p=0.01) and elevated baseline eCCl (p=0.03). Preoperative inotrope usage was found to significantly reduce the odds of AKI in- cidence (p=0.02). Multivariate analysis demon- strated an independent correlation between AKI and longer paediatric intensive care unit stay. Patients with a day 3 postoperative tacrolimus level exceeding 15 ?g/litre were significantly more likely to develop AKI. The authors of this study believe that children receiving heart trans- plants should be classified as ‘high-risk’ for AKI and should be closely monitored. Studies have also found creatinine kinase-MB (CK-MB) and heart-type fatty acid binding protein (h-FABP) independently and strongly projected postoper-ative AKI incidence.FLUID MANAGEMENTFluid management plays a major role in preven- tion and subsequent treatment of AKI. When the balance between intravascular and extracellular fluid compartments is disturbed, redistribution of fluids may be hindered. The primary endpoint of fluid treatment is to restore renal perfusion via increasing intravascular volume. The gener- al types of fluids are colloids, albumin, gelatin, and crystalloids. The debate as to which type of fluid to use has always been a matter of debate. Hypertonic fluids are more likely to remain in the intravascular compartment, and most likely prove to be more effective than hypotonic fluids in patients with depleted intravascular volume. It is suggested that synthetic colloids are avoided in patients with AKI or at risk for AKI and that balanced salines are the best mode of fluids for AKI treatment.Fluid overload in patients with AKIIt is believed that AKI ensues due to systemic hy- potension with resultant renal ischaemia. Thus,Fluid management plays a major role in prevention and subsequent treatment of AKI.traditionally many practitioners have attempt- ed to “cure” AKI by supplying the patient with large volumes of fluids to restore intravascular volume and renal function. However, this course of treatment may cause fluid overload (FO), es- pecially when oligoanuric. Although it is unclear whether oedema caused by FO has any direct causal effect on AKI, oedema causing abdom- inal compartment syndrome can cause tubule compression, further retention of water and salt, and diminished renal blood flow, inducing AKI.To manage FO, the goal is to initiate a neu- tral or negative fluid balance. Current treatment approaches include diuretics and RRT. Howev- er, each has its own disadvantages. Patients may develop ‘diuretic resistance’, imbalanced electrolytes, and further decline in renal integ-Practice Points?AKI is relatively common in children admitted to paediatric intensive care.?The incidence of AKI in any setting depends upon the precise definition used, but the presence of AKI is associated with increases in morbidity and mortality.?Sepsis is one of the important causes of AKI which leads to increased duration of ventilation and ICU stay.?Use of low-dose dopamine or diuretics does not appear to improve outcomes, although both may increase urine output.rity. In terms of RRT, intermittent haemodialysis may trigger intradialytic hypotension. Therefore, continuous renal replacement therapy (CRRT) is favoured in order to maintain haemodynamic stability and prevent further renal injury.Other possible treatment methods include adenosine receptor antagonists such as theo- phylline. Although diuretics may restore urine output, research suggests no significant differ- ence in prevention of renal damage. Addition- ally, diuretics such as furosemide have been found to inhibit Na-K ATPase, causing further ischaemia. One experimental method of treat- ment includes ‘renal-dose’ dopamine, a dosage of 0.5 to 3–5 ?g/kg/minute. Dopamine serves as a vasodilator to restore renal blood flow and urine output, however this method of treatment has not been proven to be effective in AKI for increasing survival and is no longer promoted.Electrolyte balanceAKI frequently results in uraemia, characterized by elevated levels of creatinine in plasma, met- abolic acidosis, hyperkalaemia, oliguria, and reduced consciousness if AKI is severe enough during acute phase of disease. Serum potas- sium and ECG should be monitored closely for hyperkalaemia and ensure levels over 6.5 mmol/litre are quickly treated. Monitoring of ac- id-base balance is essential as well, and one may administer IV bicarbonate for treatment of acidosis in the face of persistence despite cor-rected hypovolaemia/hypotension. Lastly, ion- ized calcium should be monitored as well and treated if levels reach less than 1.0 mmol/litre, especially since treatment of acidosis could fur- ther decrease calcium levels.CONCLUSIONAKI is a condition that adversely affects outcome in critically ill paediatric patients. Various com- plications may stem from this complication both early and later in life. Early detection and treat- ment of AKI result in better outcomes. The med- ical field has come a long way in defining and treating AKI, but there is always room to improve management strategies.Further Reading1. Shah SR, Tunio SA, Arshad MH, et al. Acute kidney injury recognitionand management: a review of the literature and current evidence. Glob J Health Sci 2016; 8: 120–4.2. Devarajan P. Acute kidney injury in children: clinical features, etiology, evaluation, and diagnosis. In: UpToDate, Mattoo TK and Kim MS (Ed), UpToDate.3. Sutherland SM, Ji J, Sheikhi FH, et al. AKI in hospitalized children: epi- demiology and clinical associations in a national cohort. Clin J Am Soc Nephrol 2013; 8: 1661–9.4. Mehta L, Kellum JA, Shah SV, et al. Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007; 11: R31.5. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Inju- ry Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Inter; 2(suppl 2012): 1–138.6. Fujita E, Nagahama K, Shimizu A, et al. Glomerular capillary and en- dothelial cell injury is associated with the formation of necrotizing and crescentic lesions in crescentic glomerulonephritis. J Nippon Med Sch2015; 82: 27–35.7. Menon S, Kirkendall ES, Nguyen H, Goldstein SL. Acute kidney injury associated with high nephrotoxic medication exposure leads to chronic kidney disease after 6 months. J Pediatr 2014; 165: 522–7.8. Patzer L. Nephrotoxicity as a cause of acute kidney injury in children.Pediatr Nephrol 2008; 23: 2159–73.9. Humphreys BD, Soiffer RJ, Magee CC. Renal failure associated with can- cer and its treatment: an update. J Am Soc Nephrol 2005; 16: 151–61.10.Baron F, Deprez M, Beguin Y. The veno-occlusive disease of the liver.Haematologica 1997; 82: 718–25.11.Leventhan TM, Liu KD. What a nephrologist needs to know about acute liver failure. Adv Chronic Kidney Dis 2015; 22: 376–81.12.Matloff RG, Aronon R. The kidney in pediatric liver disease. Pediatr Gas- troenterol 2015; 17: 36.13.Bucholz EM, Whitlock RP, Zapitelli M, et al. Cardiac biomarkers and acute kidney injury after cardiac surgery. Pediatrics 2015; 135: e945–56.14.Godin M, Bouchard J, Mehta RL. Fluid balance in patients with acute kidney injury: emerging concepts. Nephron Clin Pract 2013; 123: 238–45.15.Yerram P, Karuparthi PR, Misra M. Fluid overload and acute kidney injury.Hemodialysis 2010; 14: 348–54.? 2017 Elsevier Ltd. All rights reserved. Initially published in Paediatrics andChild Health 2017;27(5):233–237.About the AuthorsRupesh Raina is a Consultant Nephrologist in the Department of PediatricNephrology at Akron Children Hospital, Akron and Akron General Medical Center, Cleveland Clinic Foundation, Akron, OH, USA. Conflict of interest: none declared.Abigail Chauvin is a Second-Year Medical Student at Northeast Ohio MedicalUniversity of Rootstown, Ohio, USA. Conflict of interest: none declared.Akash Deep is a Consultant Paediatric Intensivist at King’s College Hospital, Denmark Hill, London, UK. Conflict of interest: none declared.Bleeding in Early PregnancyPun Ting Chung MBBS, FHKAM (O&G), FRCOG; Yung Shuk Fei Sofie MBBS, FHKAM (O&G); Wan Hei Lok Tiffany MBBS, FHKAM (O&G)INTRODUCTIONVaginal bleeding commonly occurs in pregnancy. More than 20% of preg- nant women with successful deliveries experienced vaginal bleeding during the antenatal course.1 Two of the most important differential diagnoses for pa- tients presenting with bleeding in early pregnancy are miscarriage and ectopic pregnancy.2 SKPASSESSMENT OF BLEEDING IN EARLY PREGNANCYFor patients admitted to the ward through the Accident & Emergency De- partment, the general condition should be assessed before taking history and performing examination. Resuscitation of the patients should be performed as appropriate.History should be directed to es- tablish the possibility of pregnancy. As- sociated symptoms including abdom-inal pain and passage of tissue massVaginal bleeding commonly occurs in pregnancy. More than 20% of pregnant women with successful deliveries experienced vaginal bleeding during the antenatal course.should be asked. Risk factors of ectopic pregnancy such as history of previous ectopic pregnancy, pelvic inflammatory disease, tubal surgery, and use of as- sisted reproduction techniques should be explored.Abdominal examination is an in- dispensable assessment. Apart from helping to make the diagnosis, pres- ence of free fluid or peritoneal signs often indicates surgical treatment. The value of performing routine vaginal ex- amination is challenged.2-3 However, vaginal examination would be impor- tant for patients with severe vaginalbleeding or abdominal pain. Remov- al of products of conception from the cervix may stop bleeding. It will also ameliorate vasovagal shock as a result of distension of the cervical os. There are other advantages of vaginal exami- nations. Local causes of vaginal bleed- ing like cervical ectropion and cervical polyp can be diagnosed. Opportunis- tic screening for carcinoma of cervix can also be done. The authors are of the opinion that a vaginal examination should be done.To make a definitive diagnosis, most patients would need further investi-gations. A negative pregnancy test would rule out pregnancy related complications. The single most useful investigation for a patient with bleeding in early pregnancy is transvaginal ultrasound examination. The other important investigation is the serum human chorionic gonadotropin (hCG) level.MISCARRIAGEMiscarriage is the preferred term for pregnancy loss before 24 weeks.4 This should replace the term ‘abortion’ in a series of related conditions (Table 1). The term silent miscarriage is better becauseTable 1. Recommended Terminology for Early Pregnancy Loss and RelatedConditionsOld terminologyRecommended terminologySpontaneous abortionMiscarriageThreatened abortionThreatened miscarriage Inevitable abortionInevitable miscarriage Incomplete abortionIncomplete miscarriage Complete abortionComplete miscarriage Missed abortionSilent miscarriageSeptic abortionMiscarriage with infectionAdapted from RCOG Green-Top Guideline No. 254Table 2. Diagnostic Criteria for Silent MiscarriageUltrasound findingsManagementTransvaginal scanCRL <7 mm withno visible heartbeatPerform a second scan, a minimum of 7 days after the firstCRL ≥7 mm withno visible heartbeatSeek a second opinion on the viability and/or perform a second scan, a minimum of 7 days after the firstMSD <25 mm withno visible foetal polePerform a second scan, a minimum of 7 days after the firstMSD ≥25 mm withno visible foetal poleSeek a second opinion on the viability and/or perform a second scan, a minimum of 7 days after the firstTransabdominal scanVisible foetal pole with no visible heartbeatRecord the size of the CRL and perform a second scan, a minimum of 14 days after the firstVisible intrauterine with no visible foetal poleRecord the size of the MSD and perform a second scan, a minimum of 14 days after the firstAdapted from NICE Clinical Guideline 154.9CRL: Crown-rump length; MSD: Mean sac diameterultrasound should be done to confirm the foetal viability by detecting the foe- tal pulsation. Cardiac activity can be documented at around 5 weeks and 5 days’ gestation.7 However, a substan- tial proportion of pregnancies miscar- ried after detection of cardiac activity. In one series of patients after assisted reproduction treatment, 12.2% of preg- nancies miscarried afterward.8 The efficacy of treatment of patients with threatened miscarriage with progester- one is inconclusive.9Silent miscarriageThe clinical features are very similar to threatened miscarriage. Some patients have no symptoms at all. The uterine size may be smaller than the gesta- tional age. The ultrasound diagnostic criteria are listed in Table 2. The confir- mation by a second opinion or repeat ultrasound examination after 1 week is recommended because of the conse- quence of misdiagnosing a viable preg- nancy as miscarried.9 After a diagnosis of silent miscarriage is made, there are three options to further manage- ment. Expectant management for 1–2 weeks is the preferred management because this would minimise the risk of terminating a viable pregnancy. Also, expectant management is probably the most cost effective.10 The Nation- al Institute for Health and Care Excel- lence (NICE) suggested that an ultra- sound examination should be done if bleeding and pain have not started, or bleeding or pain are persisting and/orincreasing after 3 weeks. If bleeding‘missed miscarriage’ is considered ‘a mouthful to enunciate’ 5. The other alter- native term is ‘delayed miscarriage’ but this term could imply fault on the part of the woman or her doctors.6Threatened miscarriageThe amount of bleeding is usually not heavy. There is usually no abdomi- nal pain and the uterine size is corre- sponding to the gestational age. Pelvicand pain of the patient have subsided, a pregnancy test should be done at the end of 3 weeks.9 It is important to note that these recommendations are not supported by sufficient clinical stud-ies.11 Medical treatment is the second acceptable option. This is also cost-ef- fective12 and avoids the risk of evacu- ation of uterus. An 800 mcg of miso- prostol can be administered vaginally. The dose can be repeated if there is no bleeding or abdominal pain the next day. NICE suggested that a pregnan- cy test should be done after 3 weeks. Again, this recommendation is only based on expert recommendation. The third option is surgical evacuation of the uterus, either through electric or manu- al vacuum aspiration. A comparison of the three options can be found in Table3. The final decision should be made by the patient in the absence of con- traindications. Tissue mass obtained in the course of treatment should be sent for histological assessment to confirm intrauterine pregnancy and exclude unsuspected gestational trophoblastic disease.4Intrauterine pregnancy of uncertain viabilityA woman is considered to have an in- trauterine pregnancy of uncertain via- bility if transvaginal ultrasonography shows an intrauterine gestational sac with no embryonic heartbeat and no findings of definite pregnancy failure.13NICE suggested that an ultrasound ex- amination can be repeated in a week following a transvaginal scan. The find- ings of a prospective observational multicentre study supported this rec-ommendation.14Table 3. Three Options of Management of MiscarriageExpectant managementMedical managementSurgical managementTreatment-Single dose of800 mcg vaginal misoprostolEvacuation underMAC or GAContraindications? Evidenceof infection? Haemodynamic instability? Suspicion of ectopic pregnancy? Evidence of infection? Haemodynamic instability? Allergy to misoprostol? Suspicion of ectopic pregnancy-AdvantagesNoninvasiveLess invasiveQuickest, highest success rate;Shortest duration of bleedingDisadvantagesIncreased need for blood transfusion, unplanned admission, and intervention;Longer duration of bleedingCompared with surgical treatment:- Gastrointestinal side effects- Longer duration of pain and bleeding- More unplanned admissionsAnaesthetic and surgical risksSuccess rate14–47% (silent miscarriage);85% in 2 weeks (incomplete miscarriage)85%95%Anti-RhD prophylaxis for nonsensitised RhD-negative womenNo, if spontaneous miscarriage occurs and no intervention neededNoYesAt least 250 IUanti-D IgCostMost cost effectiveSecond most cost effectiveMost costlyIncomplete miscarriageThe patient usually has a history of passage of tissue mass apart from vaginal bleeding. There may also be history of abdominal pain. The cer- vical os is open and the uterine sizeMAC: Monitored anaesthesia careis usually smaller than the gestation- al age. There is no consensus on the ultrasound diagnostic criteria for in- complete miscarriage. Measurementof endometrial thickness or volume cannot differentiate between retained products of gestation and decidua.15The value of morphological criteria arePregnancy of unknown locationPregnancy of unknown location This is a descriptive term applied to women with a positive pregnancy test who have no evidence of either an intra-History of passage of tissue massNo passage of tissue massuterine or ectopic pregnancy on trans- vaginal ultrasound examination.17 An al- gorithm to manage patients in this state can be found in Figure 1.Available for histologyAwait histological confirmationNot available for histology>50% drop in48 hoursCheckSerum hCG (urgent)Repeat hCG as near as possible to 48 hours later (but not earlier)Change in hCG between a 50% decline and a 63% raise inclusive* *>63% rise in48 hoursRepeat TVSECTOPIC PREGNANCYEctopic pregnancy remains one of the important causes of maternal mor- tality.18 When an ectopic pregnancy ruptures, the patient develops hypo- volemic shock and may die without timely intervention. Fortunately, most patients present before rupture. The classic symptoms of ectopic preg- nancy include missed period, vaginal bleeding, and abdominal pain. Risk factors should be explored. Significant physical findings include abdominal and cervical motion tenderness andpregnancy test after 2 weeksClinical review within24 hours7–14 days later(or earlier if hCG >1,500 IU/L)adnexal mass or tenderness. In a re-cent review of literature, it was found that all components of patient history and symptoms showed limited clinical*If there are new or worsening symptoms, arrange clinical review within 24 hoursFigure 1. Management of patients with pregnancy of unknown locationAdapted from NICE Clinical Guideline 154.9value. Similarly, normal findings did not decrease the likelihood of an ectopic pregnancy.19Transvaginal ultrasound exami-nation is the most important modalityalso not sufficiently evaluated.7 The same three options are useful for man- agement after the diagnosis is made. Expectant management is probably more successful for incomplete mis- carriage when compared to silent miscarriage.16 The same option is probably also true for medical miscar- riage. To keep the local protocol sim- pler, the same protocol used for silent miscarriage can be used, although a lower dose for incomplete miscarriage should plete miscarriageThe presentation is very similar to incom- plete miscarriage, but usually both pain and bleeding should have subsided. The cervical os is closed and the uterine size should be smaller. Ultrasound examina- tion should reveal no signs of any preg- nancy tissue within the uterine cavity.7 This diagnosis should be made only if there is evidence supporting the prior presence of an intrauterine pregnancy like previous ultrasound evidence or histological evi- dence of intrauterine pregnancy.of investigation. The likelihood ratio of ectopic pregnancy in the presence of an adnexal mass and the absence of an intrauterine pregnancy was report- ed to be 111 (95% confidence interval,12–1028). Presence of extrauterine gestational sac with yolk sac and/or embryo is considered definitive evi- dence of ectopic pregnancy. The pres- ence of an inhomogeneous adnexal mass or extrauterine sac-like structure should be considered as probably ec- topic pregnancy.17 This distinction isUSG diagnostic or probably diagnostic of ectopic pregnancySuitable for expectant management- hCG ≤1,000 IU/L- hCG on decreasing trend- No haemoperitoneum- Minimal symptoms- Negative foetal cardiac pulsation- Patient’s wish (+) compliance to follow-upUnsuitable for expectant management- If hCG <1,500 IU/L, offer medical treatment as first line treatment- May be safer to check a second hCG level to confirm the absence of a normal rise when USG findings are probably diagnostic onlyExpectant managementMedical vs Surgical(hCG 1,500–5,000 IU/L)Suitable for medical treatment- No significant pain- An unruptured ectopic pregnancy with an adnexal mass smaller than 35 mm with no visible heart beat- No intrauterine pregnancy (as confirmed on ultrasound scan)- Able to return for follow-upUnsuitable for medical treatment- Ectopic pregnancy with an adnexal mass of 35 mm or larger- Ectopic pregnancy with a foetal heartbeat visible on ultrasound scan- Significant abdominal pain- Unable to return for follow-up- Medical treatment not acceptable to the woman- hCG ≥5,000 IU/LBlood tests: Complete blood picture, liver and renal function tests, and hCGNormal ALT, Cr, WBC, Plt and Serum hCG <5,000 IU/L1Unsuitable for medical treatment: ALT >2xNormalCr >120 umol/L WBC <3x109/L Plt <100x109/L hCG >5,000 IU/LNo risk factors for infertility or no fertilityLaparoscopyRisk factors for infertility eg, contralateral tube damageSalpingectomySalpingotomyMedical treatment(Methotrexate IMI50 mg/m?)Patient to check pregnancy test at 3 weeks and reassess if positiveWeekly hCGtill normalFigure 2. Management of ectopic pregnancyAdapted from NICE Clinical Guideline 1549Laparoscopic salpingectomy should be the surgery of choice for ectopic pregnancy. This can avoid the risk of persistent ectopic pregnancy whilst the reproductive outcome is similar.delivered a live birth and the other preg- nancy was ongoing at 35 weeks at the time of report.21 Serial hCG would be more helpful. In fact, the use of discrim- inatory zone was not described in the NICE guideline. Apart from making the diagnosis, the level of hCG can also help to triage a patient for the different options of management.There are also three options in the management of ectopic pregnan- cy. An algorithm to manage patients suffering from ectopic pregnancy can be found in Figure 2. Expectant management has been reported to be effective in more than a third of patients.22 They included patients in whom there is no immediate indication to perform surgery and the hCG level lower than 1,500 IU/L. A lower cut-off of 1,000 IU/L was recommended in the previous RCOG guideline.23 This op- tion was not mentioned in the current NICE guideline.Medical treatment with systemic methotrexate is a cost-effective option compared with surgery. In general, it is useful for asymptomatic patients with early ectopic pregnancy. The inadvert-ent administration of methotrexate toimportant to avoid inadvertently giving methotrexate to an early intrauterine pregnancy.cy should be avoided. It only suggests that the pregnancy may not be viable.20The pregnancy may even be proven toan undetected intrauterine pregnan- cy is the worst nightmare of medical treatment. It is thus safer to confirm the absence of a normal rise in hCG for pa- tients with a diagnosis of probable ec-Molar pregnancy and cervical ectropion are other causes of bleeding in early pregnancytopic pregnancy before administration of methotrexate.Laparoscopic salpingectomy shou- ld be the surgery of choice. This canavoid the risk of persistent ectopic preg-Checking serum hCG level is im- portant in pregnancy of unknown lo- cation. The concept of discriminatory zone has been described but the pitfalls of using it to diagnose ectopic pregnan-be viable later. In a retrospective study, there were at least 8 patients in whom no intrauterine pregnancy was ob- served when the hCG level was more than 2,000 IU/L. On follow-up, 7 of themnancy whilst the reproductive outcome is similar.24The discussion so far is mainly applicable to tubal ectopic pregnancy, which constitutes more than 90% of allectopic pregnancies. The diagnosis and management of nontubal ectopic pregnancy are different and the authors would like to refer to other publications for more information.25-26OTHER DIAGNOSESThere are other causes of bleeding in early pregnancy.Molar pregnancy is a condition which can be associated with serious sequelae. This is the reason why all tis- sue mass obtained in the course of man- agement should be sent for pathological examination.Cervical ectropion is more common- ly found. It was found in more than 10% of patients. Cervical polyp was found in2% of patients.3 In fact, in many of these patients, a normal intrauterine pregnancywas found. The ectropion or polyp couldbe the cause of the bleeding and the eas- iest way to make the diagnosis is to per- form a vaginal speculum examination.OTHER MANAGEMENT ISSUES It is important to give an anti-D rhesus prophylaxis at a dose of 250 IU (50 mi- crograms) to all nonsensitized rhesus negative women who have a surgical procedure to manage ectopic pregnan- cy or miscarriage.9 There is no need for patients who receive solely medical management for ectopic pregnancy or miscarriage, threatened miscarriage, complete miscarriage, or pregnancy of unknown location.Different patients can have a very different reactions after suffering from bleeding in early pregnancy. The doc- tor should be very sensitive towards thepossibility of developing emotional dis-tress and consider appropriate interven- tion as necessary.CONCLUSIONBleeding in early pregnancy is a com- mon condition. The most important dif- ferential diagnoses include miscarriage and ectopic pregnancy. Apart from histo- ry and physical examination, ultrasound examination and measurement of se- rum hCG are mostly required to make a diagnosis and guide management.About the authorsDr Pun Ting Chung is Consultant Gynaecologist in theDepartment of Obstetrics & Gynaecology, Queen Mary Hospital and Hon Clinical Associate Professor, The University of Hong Kong, Hong Kong.Dr Yung Shuk Fei Sofie is a Clinical Assistant Professor in the Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong.Dr Wan Hei Lok Tiffany is a specialist in Obstetrics and Gynaecology in the Department of Women’s Health & Obstetrics, the Hong Kong Sanatorium & Hospital, Hong Kong.REFERENCES1. Axelsen SM, Henriksen TB, Hedegaard M et al. Characteristics of vaginal bleeding dur- ing pregnancy. Eur J Obstet Gynecol Reprod Biol 1995;63:131–134.2. Johnstone C. Vaginal examination does not improve diagnostic accuracy in early pregnancy bleeding. Emerg Med Australas2013;25:219–221.3. Bora S, Kirk E, Bourne T. Do women with pain and bleeding in early pregnancy require a vaginal speculum examination as part of their assessment? Gynecol Obstet Invest2014;77:29–34.4. Royal College of Obstetricians and Gy- naecologists. The management of early pregnancy loss. RCOG Green Top Guideline2006;25:1–18.5. Hutchon DJ. Missed abortion versus de- layed miscarriage [letter]. Br J Obstet Gynae- col 1997;104:753.6. Morgan M. Correspondence. Missed abortion versus delayed miscarriage. Br J Obstet Gynaecol 1997;104:1099.7. Knez J, Day A, Jurkovic D. Ultrasound imaging in the management of bleeding and pain in early pregnancy. Best Pract Res Clin Obstet Gynaecol 2014;28:621–636.8. Tummers P, De Sutter P, Dhont M. Risk ofspontaneous abortion in singleton and twin pregnancies after IVF/ICSI. Hum Reprod2003;18:1720–1723.9. National Institute for Health and Clinical Excellence. Ectopic pregnancy and miscar- riage: diagnosis and initial management in early pregnancy of ectopic pregnancy and miscarriage. NICE Clinical guideline 154. Manchester (UK):NICE;2012.10. Petrou S, Trinder J, Brocklehurst P et al. Economic evaluation of alternative manage- ment methods of first-trimester miscarriage based on results from the MIST trial. BJOG2006;113:879–889.11. American College of Obstetricians and Gynecologists. Early pregnancy loss. Practice Bulletin No.150. Obstet Gynecol2015;125:1258–1267.12. You JHS, Chung TKH. Expectant, med- ical or surgical treatment for spontaneous abortion in first trimester of pregnancy: a cost analysis. Hum Reprod 2005;20:2873–2878.13. Doubilet PM, Benson CB, Bourne T et al. Diagnostic criteria for nonviable preg- nancy early in the first trimester. NEJM2013;369:1443–1451.14. Preisler J, Kopeika J, Ismail L et al. De- fining safe criteria to diagnose miscarriage:prospective observational multicentre study.BMJ 2015;351:h4579.15. Sawyer E, Ofuasia E, Ofili-Yebovi D et al. The value of measuring endometrial thickness and volume on transvaginal ultra- sound scan for the diagnosis of incomplete miscarriage. Ultrasound Obstet Gynecol2007;29:205–209.16. Sotiriadis A, Makrydimas G, Papa- theodorou S et al. Expectant, medical or surgical management of first-trimester mis- carriage: a meta-analysis. Obstet Gynecol2005;105:1104–1113.17. Barnhart K, van Mello NM, Bourne T et al. Pregnancy of unknown location: a consen- sus statement of nomenclature, definitions, and outcome. Fertil Steril 2011;95:857–866.18. Cantwell R, Clutton-Brock T, Cooper G et al. Saving Mothers’ Lives: Reviewing ma- ternal deaths to make motherhood safer:2006-2008. The Eighth Report of the Con- fidential Enquiries into Maternal Deaths in the United Kingdom. BJOG 2011;118 Suppl1:1–203.19. Crochet JR, Bastian LA, Chireau MV. Does this woman have an ectopic pregnan- cy? The rational clinical examination system- atic review. JAMA 2013;16:1722–1729.20. Barnhart KT. Early pregnancy failure: be- ware of the pitfalls of modern management. Fertil Steril 2012;98:1061–1065.21. Ko JKY, Cheung VYT. Time to revisit the human chorionic gonadotropin discrimina- tory level in the management of pregnancy of unknown location. J Ultrasound Med2014;33:465–471.22. Mavrelos D, Nicks H, Jamil A et al. Ef- ficacy and safety of a clinical protocol for expectant management of selected women diagnosed with a tubal ectopic pregnancy. Ultrasound Obstet Gynecol 2013;42:102–107.23. Royal College of Obstetricians and Gy- naecologists. The management of tubal pregnancy. RCOG Green Top Guideline2004;21:1–10.24. Mol F, van Mello NM, Strandell A et al. Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP study): an open-label, multicentre, randomized con- trolled trial. Lancet 2014;383:1483–1489.25. Ngu SF, Cheung VYT. Non-tubal ec- topic pregnancy. Int J Gynaecol Obstet2011;115:295–297.26. Ko JKY, Li RHW, Cheung VYT. Caesarean scar pregnancy: a 10-year experience. Aust N Z J Obstet Gynaecol 2015;55:64–69.Program pendidikan kedokteran berkelanjutan ini dipersembahkan olehMIMS, bekerjasama dengan Ikatan Dokter Indonesia.Setelah membaca artikel ‘Bleeding in Early Pregnancy’, jawab pertanyaan berikut kemudian kirimkan dengan menggunakan formulir jawaban yang sudah disediakan ke CME MIMS Journal of Paediatrics, Obstetrics & Gynaecology, untuk mendapatkan 2 SKP.ARTIKEL CME2 SKPBleeding in Early PregnancyJawab pertanyaan di bawah ini dengan Benar atau Salah.1. There is no need to perform pelvic examination in patients suffering from bleeding in early pregnancy because of the accuracy of ultrasound examination.2. Delayed miscarriage is a better term than silent miscarriage because most patients would have some symptoms and therefore cannot be ‘silent’.3. Silent miscarriage can be diagnosed if foetal pulsation is not detected after 6 weeks maturity.4. Expectant management is the preferred management for silent miscarriage because the risk of terminating a viable pregnancy would be minimised with other treatments.5. It is proven that repeating a vaginal scan after 7 weeks is the most cost effective approach for intrauterine pregnancy of uncertain viability.6. Endometrial thickness of less than 1 cm confirmed the diagnosis of complete miscarriage.7. The presence of an inhomogenous adnexal mass or extrauterine sac-like structure and absence of an intrauterine gestational sac confirm the diagnosis of ectopic pregnancy.8. An hCG level of more than 2,000 IU/L without evidence of intrauterine gestation on transvaginal ultrasound examination is not compatible with a normal intrauterine pregnancy.9. Expectant management is not an option for the management of ectopic pregnancy.10. Laparoscopic salpingotomy should be considered the surgical treatment of choice because of the superior reproductive outcome. ................
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