INDONESIA

ISSN 2411-0183
JUL/AUG 2017
VOL. 43 NO. 4

JOURNAL OF PAEDIATRICS,
OBSTETRICS & GYNAECOLOGY

YOUR PARTNER IN PAEDIATRIC, OBSTETRIC & GYNAECOLOGY PRACTICE

GYNAECOLOGY
Colposcopy and
Cervical Intraepithelial
Neoplasia

OBSTETRICS
Analgesia in Labour
and Delivery

CME ARTICLE
Bleeding in Early
Pregnancy

JUL/AUG 2017 VOL. 43 NO. 4
Editorial Board
Board Director, Paediatrics
Professor Pik-To Cheung
Associate Professor, Department of Paediatrics and Adolescent Medicine
The University of Hong Kong, Hong Kong
Board Director, Obstetrics and Gynaecology
Professor Pak-Chung Ho
Director, Centre of Reproductive Medicine
The University of Hong Kong - Shenzhen Hospital, China
Professor Biran Affandi
University of Indonesia, Indonesia
Professor Hextan
Yuen-Sheung Ngan
The University of Hong Kong, Hong Kong
Professor Kenneth Kwek
KK Womens and Childrens Hospital,
Singapore
Professor Kok Hian Tan
KK Womens and Childrens Hospital,
Singapore
Professor Dato
Dr. Ravindran Jegasothy
Dean Faculty of Medicine,
MAHSA University, Malaysia
Associate Professor Daisy Chan
Singapore General Hospital, Singapore
Associate Professor Raymond
Hang Wun Li
The University of Hong Kong, Hong Kong
Adjunct Associate Professor
Ng Kee Chong
Division of Medicine & Academic Clinical
Program (Paediatrics), c/o KK Womens and
Childrens Hospital, Singapore
Professor Seng-Hock Quak
National University of Singapore,
Singapore
Adjunct Associate Professor
Tan Ah Moy
KK Womens and Childrens Hospital,
Singapore
Dr. Catherine Lynn Silao
University of the Philippines Manila,
Philippines
Dwiana Ocviyanti, MD, PhD
University of Indonesia, Indonesia
Dr. Karen Kar-Loen Chan
The University of Hong Kong,
Hong Kong
Dr. Kwok-Yin Leung
The University of Hong Kong,
Hong Kong
Dr. Mary Anne Chiong
University of the Philippines Manila,
Philippines
Dr. Wing-Cheong Leung
Kwong Wah Hospital, Hong Kong,
Hong Kong
MIMS JPOG JUL/AUG 2017 i
CONFERENCE
American Society of Clinical Oncology
(ASCO) 2017 Annual Meeting, June 2-6,
Chicago, Illinois, US
133
Pregnancy still possible after breast cancer
Chronic disease incidence declines over time in
childhood cancer survivors
JOURNAL WATCH
134
Autism spectrum disorder:
Updated guidelines for GPs
Triponderal mass index superior to
BMI for evaluating body fat during
adolescence
Isolated maternal hypothyroxaemia
in third trimester linked to pre-eclampsia
135
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
age
 MIMS JPOG JUL/AUG 2017 iii

JUL/AUG 2017 VOL. 43 NO. 4

REVIEW ARTICLE
GYNAECOLOGY
CEO Yasunobu Sakai
Managing Editor Elvira Manzano
Medical Editor Elaine Soliven
Designer Sam Shum
137
Production Edwin Yu, Ho Wai Hung, Steven Cheung, Agnes Chieng
Circulation Christine Chok Colposcopy and Cervical Intraepithelial
Accounting Manager Minty Kwan
Advertising Coordinator Pannica Goh
Neoplasia
Cervical cancer is caused by certain
Published by:
MIMS (Hong Kong) Limited
types of human papillomavirus (HPV)
27th Floor, OTB Building, 160 Gloucester Road, Wan Chai, Hong Kong and is preceded by a long precancerous
Tel: (852) 2559 5888 | Email: enquiry@mimsjpog.com
stage of cervical intraepithelial neoplasia
(CIN). Cervical cancer can be prevented
by successful introduction of HPV
immunization programme and screening
Enquiries and Correspondence using HPV testing, cytology, and colposcopy.
China Philippines Aslam Shiraz, Tarang Majmudar
Yang Xuan Kims Pagsuyuin, Rowena Belgica
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Analgesia in Labour and Delivery
Tel: (82 2) 3019 9350 Nguyen Thi My Dung Pain due to labour requires specic
Email: inquiry@kimsonline.co.kr Tel: (84 8) 3829 7923
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Fatmawati, Fransiska Simamora, the basic principles of acute pain
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Tiffany Collar, Sumitra Pakry, offered. This review considers the basic
Sharon Ong, Wong Wen Dee
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scenarios. The type of analgesia given will determine where labour
takes place and this will be reected in each case.
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JUL/AUG 2017 VOL. 43 NO. 4

REVIEW ARTICLE MIMS JPOG welcomes papers in the

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PAEDIATRICS
Review Articles
Comprehensive reviews providing the latest clinical information
160 on all aspects of the management of medical conditions affecting
children and women.
Acute Kidney Injury in Paediatric Critical Care
Incidence of acute kidney injury (AKI) is Case Studies
gradually increasing in children admitted Interesting cases seen in general practice and their management.
to critical care units partly because of
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Vignettes of illustrated cases with clinical photographs.
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CONTINUING
MEDICAL EDUCATION
169
Bleeding in Early Pregnancy 2 SKP

Vaginal 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 Tiffany

The Cover:
Acute Kidney Injury in Paediatric Critical Care
2017 MIMS Pte Ltd

Peggy Tio, Designer

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CONFERENCE COVERAGE
American Society of Clinical Oncology (ASCO) 2017 Annual Meeting, June 2-6, Chicago, Illinois, US
Elaine Soliven reports
Pregnancy still possible
after breast cancer
Women 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], 0.701.26; p=0.68) or ER-neg-
ative BC (HR, 0.75, 95 percent CI,
0.531.06; 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,
0.601.18; 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, 0.360.90; p=0.01).
Its 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 time
in childhood
cancer survivors
The 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 Childrens Research Hos-
pital in Memphis, Tennessee, US.
Researchers gathered data from
the CCSS* cohort and analysed
23,601 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-
MIMS JPOG JUL/AUG 2017 133
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], 0.590.73) and subsequent
malignant neoplasms (2.4 percent vs
1.6 percent, HR, 0.85, 95 percent CI,
0.760.96) 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 Study
Dr 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
MIMSJPOG JUL/AUG 2017
2017
P the American Psychiatric Association.
Paediatrics
Autism spectrum disorder:
Updated guidelines
for GPs
Autism 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 Statistical
Manual of Mental Disorders (DSM-5) of
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 1224 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 adolescence
Triponderal 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 and
Nutrition Examination Survey (1999
2006), researchers analysed cross-sec-
tional dual-energy X-ray absorptiometry
and anthropometric data from 2,285
non-Hispanic white participants aged
829 years to determine changes in
JOURNAL WATCH PEER REVIEWED
body 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 BMI
8.0 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 Pediatr
2017.doi:10.1001/jamapediatrics.2017.0460.
O
Obstetrics
Isolated maternal
hypothyroxaemia in third
trimester linked to pre-eclampsia
Researchers in China have shown that
isolated maternal hypothyroxaemia (IMH)
JOURNAL WATCH PEER REVIEWED MIMS JPOG JUL/AUG 2017 135

detected 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.
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.
ical failure was defined as >1,000 copies
HIV-1 RNA/mL.
At 1-year postpartum, three wom-
en were found to have virological fail-
ure, and seven were affected by the
18-month time point. No vertical trans-
mission of HIV-1 was noted among the
49 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
Low rate of DRMs, vertical option B+ for PMTCT. PLoS ONE 2017;12:e0178297

transmission of HIV-1 among

women treated with Option B+

The 2012 WHO guidelines recommend

In the study, first (week 912) and
third (week 3236) trimester serum sam-
ples were collected from 6,031 mothers
(aged 2143 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 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-
136 MIMS JPOG JUL/AUG
MIMSJPOG JUL/AUG 2017
2017 JOURNAL WATCH PEER REVIEWED

(10.5 percent), and yeast infection (3.7
G percent). HR-HPV (7 percent) was de-
tected and significantly correlated with
Gynaecology abnormal cervical cytology (p<0.0001).
Moreover, the risk of HR-HPV infection
was significantly increased by the pres-
levels 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

High prevalence of lower
genital tract infection among
women in Beijing, China
The 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 2070
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
ence of bacterial vaginosis (odds ra- telomere lengths with increasing age
tio, 3.0, 95 percent confidence interval, (p=0.015). Notably, shorter telomere
1.75.4; p<0.0001). length was linked to higher than average
basal cortisol levels (p=0.007) as well as
Zhang D, et al, Epidemiological investigation of the relationship
between common lower genital tract infections and high-risk greater variations in basal cortisol lev-
human papillomavirus infections among women in Beijing,
China. PLoS ONE 2017;12:e0178033. els over time (p=0.053). Nonparametric
.
bootstrapping analyses indicated that
HPAA activity mediated the effect of child
Traumatic life events affect mortality on telomere length.
cellular ageing in women The researchers suggested that
of reproductive age more large-scale longitudinal studies are
required to confirm their findings.
Women of reproductive age who suffer
Barha CK, et al, Child mortality, hypothalamic-pituitary-ad-
a traumatic life event such as the loss renal axis activity and cellular aging in mothers. PLoS One
2017;12:e0177869.
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 womens 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 cortisol
GYNAECOLOGY PEER REVIEWED MIMS JPOG JUL/AUG 2017 137

Colposcopy and Cervical

Intraepithelial Neoplasia
Aslam Shiraz MA (Cantab) MB BChir (Cantab); Tarang Majmudar MBBS MD (Mumbai, India) FRCOG

Cervical 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, signicant 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 have
the potential to reduce the morbidity associated with CIN.

INTRODUCTION est malignancies affecting young wom-

Cervical cancer is one of the common- en. In 2012, the International Agency
138 MIMS JPOG JUL/AUG 2017
REVIEW
Figure 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 13), 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. Nearly
85% 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.
GYNAECOLOGY PEER REVIEWED
AETIOLOGY AND RISK FACTORS
HPV 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, and
58 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 CIN
The 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 614 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. About
1020% of these latent infections will progress to
a productive infection. In a productive infection
(Figure 1), the virus reaches the supercial 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
supercial 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 and
GYNAECOLOGY PEER REVIEWED MIMS JPOG JUL/AUG 2017 139

Table 1. CIN Classification Systems

Dysplasia terminology Original CIN terminology Modified CIN terminology The Bethesda system (SIL) terminology
(1991)
Normal Normal Normal Within normal limits benign cellular
changes (infection or repair) ASCUS/AGUS
Atypia Koilocytic atypia, flat Low-grade CIN LSIL
condyloma, without
epithelial changes
Mild dysplasia or mild CIN 1 Low-grade CIN LSIL
dyskaryosis
Moderate dysplasia or CIN 2 High-grade CIN HSIL
moderate dyskaryosis
Severe dysplasia or CIN 3 High-grade CIN HSIL
severe dyskaryosis
Carcinoma in situ CIN 3 High-grade CIN HSIL
Invasive carcinoma Invasive carcinoma Invasive carcinoma Invasive carcinoma
CIN: 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 stratication, 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 CIN
140 MIMS JPOG JUL/AUG 2017
CIN progression
L1
E4
L1
E4
Viral DNA
Viral DNA
ET
ET
CIN1 CIN2
LSIL
DEREGULATION OF E7 LEVELS IN BASAL & PARABASAL LAYERS
Figure 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 classication of 2014
has modied the classication of intraepithelial
lesions into two grades and currently classies
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 inammation 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 has
GYNAECOLOGY PEER REVIEWED
E4
Viral DNA
ET
ET
CIN3 CaCx
HSIL Cervical cancer
INTEGRATION AND/OR SECONDARY GENETIC CHANGES
shown 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.
CGIN
This 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 classication system divides glandu-
lar lesions into two broad categories ie, border-
line changes and glandular neoplasia.
However, the disease burden related to
CGIN 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.
GYNAECOLOGY PEER REVIEWED
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 factors
Lifestyle modication 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.
MIMS JPOG JUL/AUG 2017 141
HPV vaccination
HPV 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 and
18, Gardasil against four types HPV 6, 11, 16,
and 18 and Gardasil 9 against nine types HPV
6, 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 additional
97% protection against HPV types 31, 33, 45, 52,
and 58 related cervical disease.
Overall, vaccination is likely to prevent over
70% 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 between
142 MIMS JPOG JUL/AUG 2017
HIV-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 89 years
after the initial regimen and women are still rec-
ommended to have cervical cancer screening.
Screening
Screening 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.
GYNAECOLOGY PEER REVIEWED
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 screening
In 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 July
2016. It is intended that the implementation of
HPV primary screening will be a phased ap-
proach and could take until 2019.
GYNAECOLOGY PEER REVIEWED MIMS JPOG JUL/AUG 2017 143

The key reasons for this approval were:


HPV-based primary screening provides a
6070% 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 screening
intervals.

Colposcopy
Colposcopy is the basis of secondary screen-
ing in the UK. Hans Hinselmann rst 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 magnication of the transformation zone
and its reaction to 35% acetic acid or Lugols
iodine. The transformation zone is the area
where CIN develops and is dened 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 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.
both these factors are realized will appropriate
diagnosis, counselling, and treatment occur.
Colposcopic abnormalities are graded FUTURE OF COLPOSCOPY
according to the appearance of acetowhite There are multiple adjuncts that are now
change, iodine uptake, and vascular patterns available that improve the sensitivity and/or
(eg, mosaicism, punctuation, and atypical ves- specicity of colposcopy alone. These include
sels). Thus, assessments are subjective and devices such as DySIS and Niris Imaging
prone to inter-observer variability. This variation System.
is markedly reduced for high-grade (HG) le- DySIS is a digital video colposcope that
sions and the PPV of a colposcopic impression also uses dynamic spectral imaging to evalu-
of CIN3 was noted to be 78% in a systematic ate the whitening effect of acetic acid on the
review. epithelium (Figures 3a and 3b). It produces a
144 MIMS JPOG JUL/AUG 2017
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 specicity 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 a
GYNAECOLOGY PEER REVIEWED
depth of 1.6 mm. The Niris system has a lower
sensitivity for identifying CIN2 + lesions (86.5%
vs 99%) but a similar specicity (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 insufcient evidence to justify Niris as a
cost-effective adjunct to colposcopy.
Referral criteria for colposcopy
Currently, the indications for colposcopy referral
are dened 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 reex 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/
conrmed on biopsy, consider expectant
monitoring. Over 50% of LG CIN lesions will
regress over 22 months. Treatment may be
GYNAECOLOGY PEER REVIEWED
considered 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/conrmed on biopsy,
then consider treatment.

If there is discrepancy between cytology,
histology, and colposcopy ndings, consid-
er MDT review and plan management as per
consensus opinion.
Conservative management of CIN2
Approximately 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
abnormalities
Atypical 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 is
MIMS JPOG JUL/AUG 2017 145
identied 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 women
146 MIMS JPOG JUL/AUG 2017
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 2040%) 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 national
GYNAECOLOGY PEER REVIEWED
guidelines. 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 is
insufcient for increased surveillance.
Treatment of CIN
Treatment of CIN is done using a variety of meth-
ods. All methods should be efcient 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 710 mm so
as to ensure eradication of CIN that may involve
the gland crypt.
The technique used for treatment of CIN
relies on patient-specic factors such as the pa-
tients 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 of
GYNAECOLOGY PEER REVIEWED
excisional 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 techniques
Various 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 techniques
Various 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 European
MIMS JPOG JUL/AUG 2017 147
countries. 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 broids. 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 complications
Complications 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 Monsels solution. In difficult cases, su-
tures can be placed. Secondary haemorrhage
usually occurs approximately 23 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 the
148 MIMS JPOG JUL/AUG 2017
Practice 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 specicity 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 1014 mm, 15.3% for excisions of 1519 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-UP
Patients after CIN treatment remain at risk of
recurrent disease. The risk of a future cancer is
approximately 45 times that of the background
risk and usually due to poor compliance with
GYNAECOLOGY PEER REVIEWED
follow-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 nearly
6 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 cure
After 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 Reading
1. NHSCSP Colposcopy and Programme Management NHSCSP Publi-
cation 20. March 2016.
2. RCOG Scientic Impact Paper No. 21, July 2016. Reproductive Out-
comes after Local Treatment for Preinvasive Cervical Disease.
3. Public Health England NHS Cervical Screening Programme. https://
www.gov.uk/topic/population-screening-programmes/cervical.
4. Doorbar J, Quint W, Banks L, et al. The biology and life cycle of human
papillomaviruses. Vaccine 2012; 30: F5570.
2017 Elsevier Ltd. All rights reserved. Initially published in Obstetrics,
Gynaecology and Reproductive Medicine 2017;27(6):177183.
About the Authors
Aslam Shiraz is a Specialty Registrar in the Department of Obstetrics and
Gynaecology at Hinchingbrooke Healthcare NHS Trust, Huntingdon, UK.
Conicts 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 Ofcer representing the Eastern Region. Conicts of
interest: none declared.
Filler_ads_4C_206x276mm_Non-MSE.pdf 4 22/5/17 5:48 pm
OBSTETRICS PEER REVIEWED MIMS JPOG JUL/AUG 2017 149

Analgesia in Labour
and Delivery
Andy Chu MBBS; Samson Ma BMedSci BMBS MRCP FRCA; Shreelata Datta BSc(Hons) MBBS MRCOG LLM

Pain is dened 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 specic 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 reected in each case. Specically, 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.

INTRODUCTION uctuate from moment to moment de-

Analgesia in labour is complex and can pending on the stage of labour; each
150 MIMS JPOG JUL/AUG 2017
Management 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 classied into
regional and nonregional analgesia, with a fur-
ther sub-classication 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, difcult 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 A and C af-
OBSTETRICS PEER REVIEWED
ferent bres through the sympathetic nerves
to the sympathetic chain. The pain is therefore
felt at T10L1 dermatomes. Cervical pain is
carried to the S2, 3 dermatomes via parasym-
pathetic pelvic splanchnic nerves. A bres are
thin and myelinated with a moderate speed of
signal conduction. These bres transmit acute,
sharp pain. C bres are unmyelinated and have
a slower conduction velocity. C bres 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 A bres via the pudendal nerves,
affecting the S2S4 dermatomes.
Case 1: Home/midwifery led unit
A 30-year-old G3P3 woman in early labour, con-
tracting moderately every 34 minutes.
It is possible for labouring women to require
minimal analgesia, particularly in the multiparous
OBSTETRICS PEER REVIEWED
patients. 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 signicant 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 ward
A 26-year-old primiparous patient with a histo-
ry of pre-eclampsia (not requiring medication).
She is 5 cm dilated, contracting 34 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 bene-
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 ow to the
foetus.
Epidural analgesia
Regional 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 labour
MIMS JPOG JUL/AUG 2017 151
Spinal cord
Dura mater
Interspinous ligament
Epidural space
with anaesthesia
Supraspinous
ligament
Ligamentum flavum
Subarachnoid space
Figure 1. Insertion of Tuohy needle into the epidural space
ward where monitoring can occur. An epidural
is a neuraxial technique which offers reliable,
effective, and exible analgesia to patients in
labour. Importantly, drugs used in this method
are not spread systemically. As shown in Figure
1, 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 exible
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 needing
152 MIMS JPOG JUL/AUG 2017
Table 1. Contraindications for Regional Anaesthetic Blocks
Absolute Relative
Maternal refusal Signicant haemorrhage is
expected
Local infection Untreated systemic sepsis
Uncorrected hypovolaemia Certain cardiac diseases shunts,
where rapid BP changes are not
tolerated
Coagulopathy (platelets <75 Previous spinal injuries or
x 109/litre, use of antiplatelet surgeries
agents such as clopidogrel)
Raised intracranial pressure
to 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 bres inhi-
bition. This should be anticipated and managed
as appropriate with vasopressors such as me-
taraminol or phenylephrine.
Epidurals can provide other benets 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 babies
OBSTETRICS PEER REVIEWED
immediately 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 than
6 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 risk
OBSTETRICS PEER REVIEWED
of 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 labour
Where 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 relief
of labour pain. The nerve pathways blocked are
demonstrated 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
(S2S4) 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 210 minutes from injection.
It can be difficult to administer and is therefore
MIMS JPOG JUL/AUG 2017 153
Paravertebral
Segmental epidural blocks T10L1
Lumbar sympathetic
Low caudal/true
saddle block
Sacral nerve-root
blocks S2S4
Paracervical
block S2S3
Pudendal
block S2S4
Figure 2. Nerve pathways transmitting labour pain and the available nerve blocks
that can be used to block them
not 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 ward
A 30-year-old primiparous woman who is 8 cm
dilated contracting 3:10. Platelet count was 40 x
109/litre with contraindications to a regional an-
algesic approach.
Mx issues: Besides controlling this patients
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-
154 MIMS JPOG JUL/AUG 2017
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-
tivelyit is delivered using a mouth nozzle held
OBSTETRICS PEER REVIEWED
by the patient. The gas is inhaled and reaches
a peak effect by 2030 secondsideal 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-
OBSTETRICS PEER REVIEWED MIMS JPOG JUL/AUG 2017 155

dation, and hypotension. As pethidine is highly

lipid-soluble, it crosses the placenta and foetal ex-
posure to this drug is maximal at 23 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 within
4 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 and
12 hours, respectively. Despite being signicantly
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- PCA is only considered in modern obstetric units when epidural had been
ministration, low cost, and patients perception of declined or contraindicated.
reduced risk compared to epidurals.
Diamorphine is not commonly used in ob- Remifentanil is a relatively new -recep-
stetric units across the nation. It is more lipid-sol- tor agonist. It is even more potent than fenta-
uble than morphine and therefore more potent nyl and is described as ultra short-acting,
and has a faster onset of action. While diamor- with an onset period of 1 minute and constant
phine provides good analgesia, it is found that the context-sensitive half-life of 3.5 minutes. This
length of labour is signicantly increased with its property of remifentanil makes it an ideal can-
use so therefore more pain is experienced overall. didate for PCA in labour analgesia since even
prolonged use will not cause accumulation in
Patient-controlled analgesia the tissue.
Patient-controlled analgesia (PCA) refers to However, PCA is not considered first-line for
self-administration of intravenous opioid drugs labour analgesia as medication is administered
by a preset intravenous infusion pump. This systemically side effects can affect mother and
is set up by anaesthetists on labour ward and foetus. PCA requires close supervision to avoid
allows each patient to receive an appropriate maternal hypoventilation, so the patient must
dosage of analgesics suitable to their respective be on labour ward and the lack of adequately
needs at a particular time. Fentanyl and remifen- trained staffs to care for patients with it is a con-
tanil are commonly used. Both are potent syn- traindication for use. Therefore, PCA is only con-
thetic opioids with rapid onset and short duration sidered in modern obstetric units when epidur-
of action. Fentanyl has a potency of roughly 100 al had been declined or contraindicated or in
times that of morphine but crosses the placenta situations where systemic use resulting in foetal
quickly and can accumulate in the foetus if large harm is not an issue such as in intrauterine foetal
doses are used. death with normal delivery.
156 MIMS JPOG JUL/AUG 2017
A patient with total spinal block will require ventilatory and circulatory support.
Case 4: Operating theatre
A 30-year-old primiparous woman requiring
an elective caesarean section (CS) for breech
presentation
Data 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 anaesthetic
In 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.
OBSTETRICS PEER REVIEWED
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. Bupivacaine
0.5% 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,
OBSTETRICS PEER REVIEWED
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 delivery
By 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 12 hours postop-
eratively and can be done so by a nurse or an
anaesthetist.
Combined spinal epidural
The 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.
MIMS JPOG JUL/AUG 2017 157
Extension to T4 level
for emergency CS
General area of numbness
from T8T10 level epidural
for contraction pain
EPIDURAL DURING LABOUR
Caudal extension to T4 level is required for emergency CS by top-up
Figure 3. Area of nerve block provided by an epidural analgesia for contraction
pain (T8T10)
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 12 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.
158 MIMS JPOG JUL/AUG 2017
Practice Points
The normal WHO method of analgesia does not offer the best
analgesia during this period.
Patients perception and acceptance of what is controlled pain
relief is just as important as providing the appropriate analgesia.
Patients 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 theatre
A 29-year-old primiparous patient requiring an
emergency category 1 CS for foetal distress at
3 cm
CS are classified from category 14 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-threatening
General anaesthetic
Category 24 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-
OBSTETRICS PEER REVIEWED
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 prior
to 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 DELIVERY
Analgesia should be prescribed as per the WHO
analgesic ladder. This algorithm was initially cre-
OBSTETRICS PEER REVIEWED MIMS JPOG JUL/AUG 2017 159

ated to treat cancer pain, but its stepwise ap- Step 3

proach has been applied to clinical situations in- Strong opioid
for moderate
cluding acute pain (see Figure 4). The principle Step 2 to severe pain
is to initially treat with the simplest drug and add Week opioid (eg, morphine)
for mild to nonopioid
on more potent analgesia in a stepwise fashion. adjuvant
moderate pain
This ensures a multimodal approach, which in- Step 1 (eg, codeine)
nonopioid Pain persisting
creases efcacy, and reduces the accumulative Nonopioid adjuvant
(eg, aspirin, or increasing
side-effect proles of the drugs. Patients often
paracetamol, Pain persisting
request the strongest analgesics and may ques- or NSAID) or increasing
adjuvant Pain controlled
tion physicians when given weaker medications.
It is important to explain the WHO model to pa-
tients as this allows the patient to understand the Figure 4. Stepwise approach recommended by the WHO analgesia ladder
rationale behind their treatment.
Strong opioids like morphine should be
prescribed in conjunction with their predeces- Epidural
sors, and not alone at the very beginning in or-
der to exploit the synergistic effects of combined
PCA using
analgesia. fentanyl/
remifentanil
Patients may question about the safety of these
drugs in terms of breastfeeding. Morphine delivered IM/IV
via PCA method can be transferred through breast morphine or
diamorphine
milk but it does not seem to cause adverse foetal If epidural
Entonox contraindicated,
respiratory depression, possibly from signicant Pethidine
declined, or
fist-pass metabolism. NSAIDs, apart from aspirin, impossible
are considered safe to use as well. Natural methods
(positioning,
breathing exercises,
CONCLUSION hydrotherapy,
mobilizing, and TENs)
Whilst there is no official pain ladder when deal-
Simple analgesics:
ing with women who are in labour, Figure 5 out- paracetamol Increasing/persisting pain
lines a generic approach which can be applied
to patients in labour. Patients will have different
Figure 5. Managing pain in labour the 'Obstetric Iabour' pain ladder
requirements and may have prearranged expec-
tations and successful labour analgesia can be
challenging for individual patients, with different 4. Rucklidge M. Analgesia for labour. Anaesthesia UK ATOTW Archive.
http://www.frca.co.uk/article.aspx?articleid=100551 (accessed 16 Jul
approaches needed at different stages. All preg- 2014).
5. The Royal College of Obstetricians & Gynaecologists. Green-top Guide-
nant women should discuss analgesia in labour line No. 26: Operative vaginal delivery. https://www.rcog.org.uk/globalas-
sets/documents/guidelines/gtg26.pdf.
during their antenatal appointments, document-
ing their preferred methods in their birth plan. 2017 Elsevier Ltd. All rights reserved. Initially published in Obstetrics, Gy-
naecology and Reproductive Medicine 2017;27(6):184190.
This may need to be revised or reaffirmed once
the patient is in established labour.
About the Authors
Andy Chu is a CT1 in Anaesthesia at Kingston Hospital NHS Trust, Kingston
upon Thames, UK. Conicts of interest: none declared.
Further Reading
1. Allman K, Wilson I. Oxford handbook of anaesthesia. 4th Edn. New York:
Samson Ma is an ST6 in Anaesthesia at St Georges Hospital NHS Trust,
Oxford University Press, 2016.
2. Aitkenhead A, Moppett I, Thompson J. Smith & Aitkenheads textbook of London, UK. Conicts of interest: none declared.
anaesthesia. 6th edn. Elsevier Limited, 2013.
3. Chestnut DH. Obstetric anaesthesia: principles and practice. 3rd edn. Shreelata Datta is a Consultant Obstetrician and Gynaecologist at Kings Col-
2004. Philadelphia: Elsevier Mosby, 2004. lege Hospital NHS Trust, London, UK. Conicts of interest: none declared.
160 MIMS JPOG JUL/AUG 2017 PAEDIATRICS PEER REVIEWED

Acute Kidney Injury

in Paediatric Critical Care
Rupesh Raina MD; Abigail Chauvin; Akash Deep FRCPCH MD

Incidence 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 definitions, its inability to accurately reflect kidney
function has resulted in problems for clinical research in paediatric AKI. This has
resulted in the use of more than 35 definitions of AKI in clinical studies, ranging from
small changes in serum creatinine to requirement for dialysis. Therefore, comparisons
among studies are difficult, 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 definitions used for AKI, presence of AKI in various critical
care conditions (bone marrow transplant, liver, sepsis, cardiac, and primary renal
conditions leading to glomerulonephritis), and outline the basic management.

INTRODUCTION radic failure and rapid loss of renal func-

AKI is a complex condition with numer- tion. It is fairly new terminology for what
ous pathologies, in which there is spo- was previously referred to as acute
PAEDIATRICS PEER REVIEWED
kidney failure. AKI is detected by a marked de-
crease in glomerular ltration 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% and
30% 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).
EPIDEMIOLOGY
The 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 1518 years. Additionally, neonates have
a signicantly 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 straight
MIMS JPOG JUL/AUG 2017 161
segment 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 AKI
Acute tubular necrosis (ATN) results from renal
ischaemia-reperfusion injury. Due to hypoxia,
accumulation of metabolites, and insufcient 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 inammation, weakening the endothe-
lium. Increased vascular permeability causes
uid 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) constitutes
2% 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 due
162 MIMS JPOG JUL/AUG 2017 PAEDIATRICS PEER REVIEWED

Table 1. RIFLE Guidelines from Bellomo, et al, 2004

RIFLE Glomerular filtration rate (GFR) Urine output (UO) Sensitivity vs

specificity
Categories of Risk SCr 1.5 times baseline or GFR >25% <0.5 mL/kg/hour for 6 hours Highly sensitive
kidney dysfunction
Injury SCr 2 times baseline or GFR >50% <0.5 mL/kg/hour for 12 hours

Failure SCr 3 times baseline or 4 mg/dL; <0.3 mL/kg/hour (oliguria) for 24 hours Highly specific
GFR 75% (or anuria for 12 hours)

Clinical outcomes Loss of Persistent AKI

function RRT >4 weeks

ESRD End-stage renal disease

Dialysis >3 months

to a variety of conditions including congenital or Serum creatinine (SCr) is used to estimate

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 than
5%, the patient will be classied with TTP.
DIAGNOSTIC CRITERIA
AKI 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 denitions
of AKI in order to more consistently treat and
evaluate patients.
RIFLE
In May 2002, the Acute Dialysis Quality Initiative
group (ADQI) met in Vicenza, Italy to establish
a more concrete denition 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.
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 modi-
cation of diet in renal disease (MDRD) formula is
utilized to estimate baseline GFR. Table 1 sum-
marizes these guidelines.
AKIN
Three years later, in 2007, the AKI Network (AKIN)
published an updated version of RIFLE, and this
classication 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 benecial 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.
KDIGO
The most recent model for AKI diagnosis is by
the KDIGO Work Group. Established in 2012,
this classication is designed to further expand
upon the AKIN denition. KDIGO denes AKI
with the following criteria: at least 1.5-fold elevat-
ed SCr within the past 7 days, elevated SCr by
PAEDIATRICS PEER REVIEWED
0.3 mg/dL within 48 hours, or UO equal to or
less than 0.5 mL/kg/hour over 6 hours. See Table
3 for guidelines.
pRIFLE
In children specically, a paediatric adaptation of RI-
FLE was created, known as pRIFLE. pRIFLE differs
from typical RIFLE classications in that the classi-
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 classications:
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 SEPSIS
Studies report 4570% of AKI to be induced by
sepsis. AKI and sepsis independently increase
mortality, but combined sepsis and AKI shows a
staggering mortality of 5766%. Septic AKI oc-
curs due to a combination of alterations in mi-
crovascular blood ow, ion balance, oxidative
stress, and inammation. 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 signicantly inuence septic AKI
in paediatric patients.
Sepsis is marked by systemic arterial vas-
odilation, largely mediated by nitric oxide (NO).
Inammatory 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 efux 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.
MIMS JPOG JUL/AUG 2017 163
Table 2. AKIN Guidelines from Mehta, et al, 2007
Stage Serum creatinine Urine output
1 SCr 0.3 mg/dL or 1.52.0 <0.5 mL/kg/hour for >6 hours
times baseline value
2 SCr >2.03.0 times baseline <0.5 mL/kg/hour for >12 hours
a
3 SCr 4.0 mg/dL with acute <0.3 mL/kg/hour for 24 hours
increase of 0.5 mg/dL or or anuria for 12 hours
SCr >3.0 times baseline
a
Any patients being treated with RRT automatically are placed into stage 3.
Table 3. KDIGO Guidelines from KDIGO AKI Work Group 2012
Stage Serum creatinine (SCr) Urine output
1 SCr 0.3 mg/dL or 1.51.9 <0.5 mL/kg/hour, 612 hours
times baseline value
2 SCr 2.02.9 times baseline <0.5 mL/kg/hour, 12 hours
a
3 SCr 4.0 mg/dL or 3.0 times <0.3 mL/kg/hour, 24 hours or
baseline or in patients under anuria for 12 hours
18 years, eGFR to <35 mL/
minute/1.73 m2
a
Any 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,
nonspecic effects of arginine vasopressin can
cause myocardial infarction and reduced com-
pliance of splanchnic vessels, leading to non-
cardiogenic pulmonary oedema.
164 MIMS JPOG JUL/AUG 2017
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-
causes endothelin release, which acts on vascu-
lar endothelial cells and causes microvascular
uid leakage. Inammation also plays a central
role in septic AKI. Inammatory cytokines lead
to heterogeneous upregulation of inducible NO
synthase, damaging various regions of the mi-
crovasculature.
RAPIDLY PROGRESSIVE
GLOMERULONEPHRITIS
Rapidly 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
nonspecic response to glomerular injury, ap-
pearing as 2 layers of cells in the Bowmans
PAEDIATRICS PEER REVIEWED
space of the glomerulus, constricting the glo-
merular capillary tuft. Crescent formation is initi-
ated by holes in the glomerular basement mem-
brane (GBM), Bowmans capsule, and walls of
glomerular capillaries allowing macrophages
and coagulation factors to trigger cleavage of
brinogen to brin. Earlier commencement of
medical intervention will help to avoid long-term
damage.
NEPHROTOXIC AKI
Nephrotoxic 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-inammatory
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-
PAEDIATRICS PEER REVIEWED MIMS JPOG JUL/AUG 2017 165

plasms. One in every three patients treated with

cisplatin experiences nephrotoxicity. Proximal
tubule injury, consequent oxidative stress and
inammation, 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 ow (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 of
100 children with AKI due to exposure to high
levels of nephrotoxic medications in a noncritical
setting was performed at Cincinnati Childrens
Hospital Medical Center. Researchers found
that patients with nephrotoxin-induced AKI were
3.84 times more likely to develop 1+ signs of
CKD. Additionally, the AKI cohort was found to AKI and sepsis independently increase mortality, but combined sepsis and AKI
shows a staggering mortality of 5766%.
have signicantly decreased eGFR and higher
likelihood for hypertension and proteinuria at 6
months. Pheresis may contribute to graft versus host
To manage paediatric nephrotoxic AKI, disease (GVHD) due to differing immunologi-
cease treatment with the toxic agent as soon as cal composition to marrow. GVHD accompa-
possible and prevent exposure to future nephro- nied by renal disturbance is reported to occur
toxins to preserve renal function. Fluid therapy in 1141% of paediatric patients who receive
should target restitution of renal perfusion. In HLA-matched BMT. However, peripheral HSCT
severe cases, renal replacement therapy (RRT) collection leads to reduced rates of sepsis, cy-
may be utilized for the purpose of toxic solute topaenia, and need for nephrotoxic antibiotic
removal. therapy after transplantation.
Sinusiodal obstruction syndrome (SOS),
AKI IN BONE MARROW also referred to as veno-occlusive disease
TRANSPLANTATION (VOD), commonly occurs with BMT. The exact
AKI is a common complication of haematopoie- pathophysiology is not yet known, but current
tic stem cell transplantation (HSCT), otherwise literature points to injury to hepatic sinuos-
commonly known as bone marrow transplants. oids. Despite lack of empirical evidence about
Patients with HSCT-induced AKI requiring RRT SOS-induced paediatric AKI in BMT, it is well
have a disappointingly low survival rate of 42%. known that SOS/VOD is a signicant risk factor
It is reported that the incidence of paediatric for AKI development. AKI in SOS is thought to
HSCT-induced AKI is between 25% and 30%. pathologically behave similarly to hepatorenal
166 MIMS JPOG JUL/AUG 2017
syndrome (HRS) with regards to haemodynam-
ic shifts, as well as liver impairment resulting in
hypoalbuminaemia, uid 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
debrotide tends to be the drug of choice.
AKI IN LIVER DISEASE
AKI 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 specic 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 uctuations, unbalancing uids
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 not
PAEDIATRICS PEER REVIEWED
completely 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, uid management will differ: in prerenal AKI,
uid supplementation is necessary to elevate
the intravascular volume while in intrarenal AKI
decreasing uids 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 Modication 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 DISEASE
AKI 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, 15% required
RRT for AKI, and those patients additionally have
a heightened mortality rate of 60%.
PAEDIATRICS PEER REVIEWED MIMS JPOG JUL/AUG 2017 167

In one study by MacDonald, et al, it was

found that AKI occurred in 73% of subjects, with
95% occurring within the rst 3 days post-trans-
plant. Signicant 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 signicantly 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 signicantly
more likely to develop AKI. The authors of this
study believe that children receiving heart trans-
plants should be classied 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 MANAGEMENT
Fluid management plays a major role in preven-
tion and subsequent treatment of AKI. When the
balance between intravascular and extracellular
uid compartments is disturbed, redistribution
of uids may be hindered. The primary endpoint
of uid treatment is to restore renal perfusion
via increasing intravascular volume. The gener-
al types of uids are colloids, albumin, gelatin,
and crystalloids. The debate as to which type of
uid to use has always been a matter of debate.
Hypertonic uids are more likely to remain in
the intravascular compartment, and most likely
prove to be more effective than hypotonic uids
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 uids for
AKI treatment.
Fluid overload in patients with AKI
It 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 uids to restore intravascular
volume and renal function. However, this course
of treatment may cause uid 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 ow, inducing AKI.
To manage FO, the goal is to initiate a neu-
tral or negative uid 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-
168 MIMS JPOG JUL/AUG 2017
Practice Points
AKI is relatively common in children admitted to paediatric intensive
care.
The incidence of AKI in any setting depends upon the precise
denition 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 signicant 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 35 g/kg/minute. Dopamine serves as
a vasodilator to restore renal blood ow 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 balance
AKI 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-
PAEDIATRICS PEER REVIEWED
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.
CONCLUSION
AKI 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 eld has come a long way in dening and
treating AKI, but there is always room to improve
management strategies.
Further Reading
1. Shah SR, Tunio SA, Arshad MH, et al. Acute kidney injury recognition
and management: a review of the literature and current evidence. Glob J
Health Sci 2016; 8: 1204.
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: 16619.
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): 1138.
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 Sch
2015; 82: 2735.
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: 5227.
8. Patzer L. Nephrotoxicity as a cause of acute kidney injury in children.
Pediatr Nephrol 2008; 23: 215973.
9. Humphreys BD, Soiffer RJ, Magee CC. Renal failure associated with can-
cer and its treatment: an update. J Am Soc Nephrol 2005; 16: 15161.
10. Baron F, Deprez M, Beguin Y. The veno-occlusive disease of the liver.
Haematologica 1997; 82: 71825.
11. Leventhan TM, Liu KD. What a nephrologist needs to know about acute
liver failure. Adv Chronic Kidney Dis 2015; 22: 37681.
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: e94556.
14. Godin M, Bouchard J, Mehta RL. Fluid balance in patients with acute
kidney injury: emerging concepts. Nephron Clin Pract 2013; 123: 23845.
15. Yerram P, Karuparthi PR, Misra M. Fluid overload and acute kidney injury.
Hemodialysis 2010; 14: 34854.
2017 Elsevier Ltd. All rights reserved. Initially published in Paediatrics and
Child Health 2017;27(5):233237.
About the Authors
Rupesh Raina is a Consultant Nephrologist in the Department of Pediatric
Nephrology at Akron Children Hospital, Akron and Akron General Medical
Center, Cleveland Clinic Foundation, Akron, OH, USA. Conict of interest:
none declared.
Abigail Chauvin is a Second-Year Medical Student at Northeast Ohio Medical
University of Rootstown, Ohio, USA. Conict of interest: none declared.
Akash Deep is a Consultant Paediatric Intensivist at Kings College Hospital,
Denmark Hill, London, UK. Conict of interest: none declared.
CONTINUING MEDICAL EDUCATION MIMS JPOG JUL/AUG 2017 169

Bleeding in Early Pregnancy 2 SKP

Pun Ting Chung MBBS, FHKAM (O&G), FRCOG; Yung Shuk Fei Sofie MBBS, FHKAM (O&G); Wan Hei Lok Tiffany MBBS, FHKAM (O&G)

INTRODUCTION
Vaginal 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.

ASSESSMENT OF BLEEDING
IN EARLY PREGNANCY
For 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 mass
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 vaginal
Vaginal bleeding commonly occurs in pregnancy. More than 20% of pregnant women
with successful deliveries experienced vaginal bleeding during the antenatal course.
bleeding or abdominal pain. Remov- gations. A negative pregnancy test would
al of products of conception from the rule out pregnancy related complications.
cervix may stop bleeding. It will also The single most useful investigation for a
ameliorate vasovagal shock as a result patient with bleeding in early pregnancy
of distension of the cervical os. There is transvaginal ultrasound examination.
are other advantages of vaginal exami- The other important investigation is the
nations. Local causes of vaginal bleed- serum human chorionic gonadotropin
ing like cervical ectropion and cervical (hCG) level.
polyp can be diagnosed. Opportunis-
tic screening for carcinoma of cervix MISCARRIAGE
can also be done. The authors are of Miscarriage is the preferred term for
the opinion that a vaginal examination pregnancy loss before 24 weeks.4 This
should be done. should replace the term abortion in a
To make a definitive diagnosis, series of related conditions (Table 1). The
most patients would need further investi- term silent miscarriage is better because
170 MIMS JPOG JUL/AUG 2017 CONTINUING MEDICAL EDUCATION

Table 1. Recommended Terminology for Early Pregnancy Loss and Related ultrasound should be done to confirm
Conditions the foetal viability by detecting the foe-
tal pulsation. Cardiac activity can be
documented at around 5 weeks and 5
Old terminology Recommended terminology days gestation.7 However, a substan-
Spontaneous abortion Miscarriage tial proportion of pregnancies miscar-
Threatened abortion Threatened miscarriage ried after detection of cardiac activity.
In one series of patients after assisted
Inevitable abortion Inevitable miscarriage
reproduction treatment, 12.2% of preg-
Incomplete abortion Incomplete miscarriage nancies miscarried afterward.8 The
Complete abortion Complete miscarriage efficacy of treatment of patients with
threatened miscarriage with progester-
Missed abortion Silent miscarriage
one is inconclusive.9
Septic abortion Miscarriage with infection

Adapted from RCOG Green-Top Guideline No. 254 Silent miscarriage

The clinical features are very similar to
threatened miscarriage. Some patients
Table 2. Diagnostic Criteria for Silent Miscarriage have no symptoms at all. The uterine
size may be smaller than the gesta-
tional age. The ultrasound diagnostic
Ultrasound findings Management criteria are listed in Table 2. The confir-
Transvaginal CRL <7 mm with Perform a second scan, a mation by a second opinion or repeat
scan no visible heartbeat minimum of 7 days after the first ultrasound examination after 1 week is
CRL 7 mm with Seek a second opinion on the recommended because of the conse-
no visible heartbeat viability and/or perform a second quence of misdiagnosing a viable preg-
scan, a minimum of 7 days after
the first nancy as miscarried.9 After a diagnosis

MSD <25 mm with
no visible foetal pole
MSD 25 mm with
no visible foetal pole
Transabdominal Visible foetal pole with
scan no visible heartbeat
Visible intrauterine with Record the size of the MSD
no visible foetal pole
Adapted from NICE Clinical Guideline 154.9
CRL: Crown-rump length; MSD: Mean sac diameter
missed miscarriage is considered a Threatened miscarriage
mouthful to enunciate . The other alter-
5
native term is delayed miscarriage but
this term could imply fault on the part of
the woman or her doctors.6
Perform a second scan, a
minimum of 7 days after the first
Seek a second opinion on the
viability and/or perform a second
scan, a minimum of 7 days after
the first
Record the size of the CRL and
perform a second scan, a minimum
of 14 days after the first
and perform a second scan, a
minimum of 14 days after the first
and pain of the patient have subsided,
The 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. Pelvic
of silent miscarriage is made, there
are three options to further manage-
ment. Expectant management for 12
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/or
increasing after 3 weeks. If bleeding
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-
CONTINUING MEDICAL EDUCATION MIMS JPOG JUL/AUG 2017 171

ies.11 Medical treatment is the second Table 3. Three Options of Management of Miscarriage
acceptable option. This is also cost-ef-
fective12 and avoids the risk of evacu-
ation of uterus. An 800 mcg of miso- Expectant Medical Surgical
management management management
prostol can be administered vaginally.
Treatment - Single dose of Evacuation under
The dose can be repeated if there is no
800 mcg vaginal MAC or GA
bleeding or abdominal pain the next misoprostol
day. NICE suggested that a pregnan- Contraindications Evidence Evidence of -
cy test should be done after 3 weeks. of infection infection
Again, this recommendation is only Haemodynamic
Haemodynamic instability
based on expert recommendation. The instability
Allergy to
third option is surgical evacuation of the Suspicion misoprostol
uterus, either through electric or manu- of ectopic Suspicion
al vacuum aspiration. A comparison of pregnancy of ectopic
pregnancy
the three options can be found in Table
3. The final decision should be made Advantages Noninvasive Less invasive Quickest, highest
success rate;
by the patient in the absence of con-
traindications. Tissue mass obtained in Shortest duration
of bleeding
the course of treatment should be sent
Disadvantages Increased Compared with Anaesthetic and
for histological assessment to confirm
need for blood surgical treatment: surgical risks
intrauterine pregnancy and exclude transfusion,
- Gastrointestinal
unsuspected gestational trophoblastic unplanned side effects
disease.4 admission, and
intervention; - Longer duration
of pain and
Longer duration of bleeding
Intrauterine pregnancy of
bleeding - More
uncertain viability unplanned
A woman is considered to have an in- admissions
trauterine pregnancy of uncertain via- Success rate 1447% (silent 85% 95%
bility if transvaginal ultrasonography miscarriage);
shows an intrauterine gestational sac 85% in 2 weeks
with no embryonic heartbeat and no (incomplete
miscarriage)
findings of definite pregnancy failure.13
Anti-RhD No, if No Yes
NICE suggested that an ultrasound ex- prophylaxis for spontaneous At least 250 IU
amination can be repeated in a week nonsensitised miscarriage anti-D Ig
following a transvaginal scan. The find- RhD-negative occurs and no
women intervention
ings of a prospective observational
needed
multicentre study supported this rec-
Cost Most cost Second most Most costly
ommendation.14 effective cost effective
MAC: Monitored anaesthesia care
Incomplete miscarriage
The patient usually has a history of
passage of tissue mass apart from is usually smaller than the gestation- of endometrial thickness or volume
vaginal bleeding. There may also be al age. There is no consensus on the cannot differentiate between retained
history of abdominal pain. The cer- ultrasound diagnostic criteria for in- products of gestation and decidua.15
vical os is open and the uterine size complete miscarriage. Measurement The value of morphological criteria are
172 MIMS JPOG JUL/AUG 2017 CONTINUING MEDICAL EDUCATION

Pregnancy of unknown location

Pregnancy of unknown This is a descriptive term applied to
location
women with a positive pregnancy test
who have no evidence of either an intra-
uterine or ectopic pregnancy on trans-
History of passage No passage of
of tissue mass tissue mass vaginal ultrasound examination.17 An al-
gorithm to manage patients in this state
can be found in Figure 1.
Available for Not available Serum hCG
histology for histology (urgent)
ECTOPIC PREGNANCY
Ectopic pregnancy remains one of the
important causes of maternal mor-
Await
histological tality.18 When an ectopic pregnancy
confirmation Repeat hCG as near as ruptures, the patient develops hypo-
possible to 48 hours later volemic shock and may die without
(but not earlier)
timely intervention. Fortunately, most
patients present before rupture. The
classic symptoms of ectopic preg-
Change in hCG
>50% drop in between a 50% >63% rise in nancy include missed period, vaginal
48 hours decline and a 63% 48 hours bleeding, and abdominal pain. Risk
raise inclusive
factors should be explored. Significant

* * physical findings include abdominal

Check
pregnancy
test after 2
weeks
*If there are new or worsening symptoms, arrange clinical review within 24 hours
Figure 1. Management of patients with pregnancy of unknown location
Adapted from NICE Clinical Guideline 154.9
also 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 suffice.
Repeat TVS
Clinical 714 days later
review within (or earlier if
24 hours hCG >1,500 IU/L)
Complete miscarriage
The 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. This7
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.
and cervical motion tenderness and
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
value. Similarly, normal findings did not
decrease the likelihood of an ectopic
pregnancy.19
Transvaginal ultrasound exami-
nation is the most important modality
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,
121028). 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 is
CONTINUING MEDICAL EDUCATION MIMS JPOG JUL/AUG 2017 173

USG diagnostic or
probably diagnostic of ectopic
pregnancy

Suitable for expectant management Unsuitable for expectant management

- hCG 1,000 IU/L - If hCG <1,500 IU/L, offer medical treatment
- hCG on decreasing trend as first line treatment
- No haemoperitoneum - May be safer to check a second hCG
- Minimal symptoms level to confirm the absence of a normal
- Negative foetal cardiac pulsation rise when USG findings are probably
- Patients wish (+) compliance to follow-up diagnostic only

Expectant management Medical vs Surgical

(hCG 1,5005,000 IU/L)

Suitable for medical treatment Unsuitable for medical treatment

- No significant pain - Ectopic pregnancy with an adnexal mass of 35 mm
- An unruptured ectopic pregnancy with an or larger
adnexal mass smaller than 35 mm with no - Ectopic pregnancy with a foetal heartbeat visible
visible heart beat on ultrasound scan
- No intrauterine pregnancy (as confirmed on - Significant abdominal pain
ultrasound scan) - Unable to return for follow-up
- Able to return for follow-up - Medical treatment not acceptable to the woman
- hCG 5,000 IU/L

Blood tests: Unsuitable for Laparoscopy

Complete blood picture, medical treatment:
liver and renal function ALT >2xNormal
tests, and hCG Cr >120 umol/L
WBC <3x109/L No risk Risk factors for infertility
Plt <100x109/L factors for infertility eg, contralateral tube
hCG >5,000 IU/L or no fertility damage
Normal ALT, Cr,
WBC, Plt and Serum
hCG <5,000 IU/L1
Salpingectomy Salpingotomy

Medical treatment
Patient to check Weekly hCG
(Methotrexate IMI
pregnancy test at 3 weeks till normal
50 mg/m)
and reassess if positive

Figure 2. Management of ectopic pregnancy

Adapted from NICE Clinical Guideline 1549
174 MIMS JPOG JUL/AUG 2017
Laparoscopic 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.
important to avoid inadvertently giving
methotrexate to an early intrauterine
pregnancy.
Molar pregnancy and cervical ectropion are other
causes of bleeding in early pregnancy
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-
CONTINUING MEDICAL EDUCATION
cy should be avoided. It only suggests
that the pregnancy may not be viable.20
The pregnancy may even be proven to
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 them
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 to
an 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-
topic pregnancy before administration
of methotrexate.
Laparoscopic salpingectomy shou-
ld be the surgery of choice. This can
avoid the risk of persistent ectopic preg-
nancy whilst the reproductive outcome is
similar.24
The discussion so far is mainly
applicable to tubal ectopic pregnancy,
which constitutes more than 90% of all
CONTINUING MEDICAL EDUCATION MIMS JPOG JUL/AUG 2017 175

ectopic pregnancies. The diagnosis
and management of nontubal ectopic
pregnancy are different and the authors
would like to refer to other publications
for more information.25-26
OTHER DIAGNOSES
There 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-
be 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. There is no need for
9
patients who receive solely medical
management for ectopic pregnancy or
miscarriage, threatened miscarriage,
complete miscarriage, or pregnancy of
unknown location.
tress and consider appropriate interven-
tion as necessary.
CONCLUSION
Bleeding 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 authors
Dr Pun Ting Chung is Consultant Gynaecologist in the
Department of Obstetrics & Gynaecology, Queen Mary
Hospital and Hon Clinical Associate Professor, The
University of Hong Kong, Hong Kong.

ly found. It was found in more than 10%
of patients. Cervical polyp was found in
2% of patients.3 In fact, in many of these
patients, a normal intrauterine pregnancy
was found. The ectropion or polyp could
Different patients can have a very
different reactions after suffering from
bleeding in early pregnancy. The doc-
tor should be very sensitive towards the
possibility of developing emotional dis-
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 Womens Health &
Obstetrics, the Hong Kong Sanatorium & Hospital, Hong
Kong.

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176 MIMS JPOG JUL/AUG 2017 CME QUESTIONS

Program pendidikan kedokteran berkelanjutan ini dipersembahkan oleh

MIMS, 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 CME 2 SKP

Bleeding in Early Pregnancy

Jawab 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.